rs145226920

Variant names:

• chr11-68933864-C-A
• rs145226920
• NM_002180.3:c.1488C>A

Your query was ambiguous. Multiple possible variants found:

• chr11-68933864-C-A
• chr11-68933864-C-T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 16P and 1B. PVS1 PP5_Very_Strong BS1_Supporting

The NM_002180.3(IGHMBP2):​c.1488C>A​(p.Cys496*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000348 in 1,606,292 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. C496C) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00037 (0 hom.)
• Consequence: IGHMBP2 NM_002180.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:20
• Conservation: PhyloP100: -0.802
• Publications: 17 publications found

Genes affected

IGHMBP2 (HGNC:5542): (immunoglobulin mu DNA binding protein 2) This gene encodes a helicase superfamily member that binds a specific DNA sequence from the immunoglobulin mu chain switch region. Mutations in this gene lead to spinal muscle atrophy with respiratory distress type 1. [provided by RefSeq, Jul 2008]

IGHMBP2 Gene-Disease associations (from GenCC):

• autosomal recessive distal spinal muscular atrophy 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• Charcot-Marie-Tooth disease axonal type 2S

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hereditary peripheral neuropathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 11-68933864-C-A is Pathogenic according to our data. Variant chr11-68933864-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 234316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000372 (541/1454036) while in subpopulation NFE AF = 0.00046 (510/1108236). AF 95% confidence interval is 0.000427. There are 0 homozygotes in GnomAdExome4. There are 272 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGHMBP2	NM_002180.3	c.1488C>A	p.Cys496*	stop_gained	Exon 10 of 15	ENST00000255078.8	NP_002171.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGHMBP2	ENST00000255078.8	c.1488C>A	p.Cys496*	stop_gained	Exon 10 of 15	1	NM_002180.3	ENSP00000255078.4

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152138 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000158 AC: 37 AN: 233468 AF XY: 0.000166

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000183

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000202

Gnomad NFE exome AF: 0.000258

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000372 AC: 541 AN: 1454036 Hom.: 0 Cov.: 31 AF XY: 0.000376 AC XY: 272 AN XY: 722552

African (AFR) AF: 0.0000599 AC: 2 AN: 33376

American (AMR) AF: 0.000161 AC: 7 AN: 43582

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25942

East Asian (EAS) AF: 0.00 AC: 0 AN: 39470

South Asian (SAS) AF: 0.00 AC: 0 AN: 84750

European-Finnish (FIN) AF: 0.000113 AC: 6 AN: 52886

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.000460 AC: 510 AN: 1108236

Other (OTH) AF: 0.000267 AC: 16 AN: 60036

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152256 Hom.: 0 Cov.: 33 AF XY: 0.0000806 AC XY: 6 AN XY: 74430

African (AFR) AF: 0.00 AC: 0 AN: 41552

American (AMR) AF: 0.000196 AC: 3 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000249 Hom.: 0

Bravo AF: 0.000117

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000148 AC: 18

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:20

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:9

Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Oct 26, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jul 15, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2, PM3, PS4_moderate, PVS1

Jul 30, 2025

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 09, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 23449687, 25439726, 15108294, 25525159, 29431110, 26709713, 31827005, 31589614, 33442022, 32573669, 32376792, 34726235, 31345219, 14681881)

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

May 02, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Cys496Ter variant has been reported in homozygous form as well as in compound heterozygous form together with missense or other nonsense variants in infants with spinal muscular atrophy with respiratory distress type 1 (SMARD1) with age onset of respiratory distress ranging from 3 - 91 days after birth (Grohmann 2003). Many affected infants presented with intrauterine growth restriction, decreased fetal movements, weak cry, congenital foot deformities due to early involvement of distal muscles of the lower limbs, eventration of the diaphragm due to a diaphragmatic paralysis, involvement of the autonomic nervous system, neurogenic changes in electromyography, decrease in motor nerve conduction velocity and absence of motor response after maximum stimulation, as well as fiber hypertrophy and atrophy on muscle biopsy (Grohmann 2003). Furthermore, Maystad et al. (2004) reported an infant who presented at 2 months with muscular weakness, at 2.5 month with respiratory distress and who died at 6 months. He carried the same p.Cys496Ter variant but a second IGHMBP2 variant was not identified (Maystad 2004). Additionally, Litvinenko et al. (2014) reported two infant siblings with p.Cys496Ter and Gln260fs compound heterozygous variants with severe spinal muscular atrophy respiratory distress 1, persistent eventration of the right hemidiaphragm, hypotonia due to hypo- and areflexia, complete paralysis of the limbs and mild contractures, electromyography showing active denervation, and total absence of IGHMBP2 enzyme activity. Finally, Cottenie et al. (2014) reported a 15 year old male with foot drop (first presenting at age 4), limb weakness, and ankle foot orthoses, who carried p.Cys496Ter and a missense variant.

Autosomal recessive distal spinal muscular atrophy 1;C4015349:Charcot-Marie-Tooth disease axonal type 2S Pathogenic:3

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The IGHMBP2 c.1488C>A (p.C496*) nonsense variant is predicted to result in an absent or aberrant protein. This variant has been observed in the compound heterozygous state in individuals with Charcot-Marie-Tooth disease type 2S or spinal muscular atrophy with respiratory distress type 1 (SMARD1) (PMID: 14506069; 15108294; 19157874; 23449687; 25439726).

Jan 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Cys496*) in the IGHMBP2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in IGHMBP2 are known to be pathogenic (PMID: 14681881, 25439726, 25568292). This variant is present in population databases (rs145226920, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with spinal muscular atrophy with respiratory distress 1 (SMARD1) (PMID: 14506069, 14681881, 19157874, 23449687, 26257172). ClinVar contains an entry for this variant (Variation ID: 234316). For these reasons, this variant has been classified as Pathogenic.

Jan 16, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal recessive distal spinal muscular atrophy 1 Pathogenic:3

Sep 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Charcot-Marie-Tooth disease, axonal, type 2S (MIM#616155), and distal hereditary motor neuronopathy, type VI (MIM#604320). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (42 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported many times as pathogenic in individuals with either spinal muscular atrophy with respiratory distress (SMARD) or Charcot-Marie-Tooth (CMT) (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and has been observed in both compound heterozygous and homozygous individuals with SMARD, and rarely in individuals with CMT (ClinVar, PMID: 25439726, PMID: 30598237). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Aug 18, 2015

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

This variant has been previously reported as disease-causing and was identified in trans with a predicted pathogenic variant in an individual with congenital hypotonia.

May 28, 2019

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Charcot-Marie-Tooth disease Pathogenic:1

Molecular Genetics Laboratory, London Health Sciences Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

IGHMBP2-related disorder Pathogenic:1

Jun 19, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The IGHMBP2 c.1488C>A variant is predicted to result in premature protein termination (p.Cys496*). This variant has been documented in several unrelated individuals, in the homozygous or compound heterozygous state, to be causative for autosomal recessive spinal muscular atrophy with respiratory distress type 1 (SMARD1; Grohmann et al. 2003. PubMed ID: 14681881; Pitt et al. 2003. PubMed ID: 14506069; Litvinenko et al. 2014. PubMed ID: 23449687). The c.1488C>T (p.Cys496*) variant was also identified in an infant presenting with muscular weakness and severe respiratory distress (Maystadt et al. 2004. PubMed ID: 15108294). In addition, this variant has been reported in the compound heterozygous state in one patient with Charcot-Marie Tooth type 2 (Cottenie et al. 2014. PubMed ID: 25439726). In summary, the c.1488C>T (p.Cys496*) variant is classified as pathogenic.

Inborn genetic diseases Pathogenic:1

Mar 23, 2020

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C496* pathogenic mutation (also known as c.1488C>A), located in coding exon 10 of the IGHMBP2 gene, results from a C to A substitution at nucleotide position 1488. This changes the amino acid from a cysteine to a stop codon within coding exon 10. This alteration has been detected in the homozygous and compound heterozygous states in patients with spinal muscular atrophy with respiratory distress type 1 (SMARD1) (Grohmann K et al. Ann. Neurol., 2003 Dec;54:719-24; Joseph S et al. Neuromuscul. Disord., 2009 Mar;19:193-5; Pitt M et al. Brain, 2003 Dec;126:2682-92; San Millan B et al. Clin. Neuropathol.;35:58-65). This alteration has also been detected in the compound heterozygous state in a patient with Charcot-Marie-Tooth disease, type 2 (Cottenie E et al. Am. J. Hum. Genet., 2014 Nov;95:590-601). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

Neurodevelopmental disorder Pathogenic:1

Jun 14, 2022

Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Charcot-Marie-Tooth disease axonal type 2S Pathogenic:1

Oct 24, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: IGHMBP2 c.1488C>A (p.Cys496X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00015 in 259950 control chromosomes (gnomAD). The variant, c.1488C>A, has been reported in the literature in one compound heterozygote affected with Charcot-Marie-Tooth disease type 2B2 (CMT2) (Cottenie_2014) and more frequently in compound heterozygotes and homozygotes affected with spinal muscular atrophy with respiratory distress type 1 (SMARD1)( Grohmann_2003). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic for CMT2.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	27
DANN	Uncertain	0.98
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.35	N
PhyloP100		-0.80
Vest4		0.91
GERP RS		-5.5
Mutation Taster		=3/197	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs145226920; hg19: chr11-68701332;