rs145226920

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

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 (★★). 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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:19

Conservation

PhyloP100: -0.802

Variant links:

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 links:

IGHMBP2 (HGNC:):

IGHMBP2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-68933864-C-A is Pathogenic according to our data. Variant chr11-68933864-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 234316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68933864-C-A is described in Lovd as [Pathogenic]. Variant chr11-68933864-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGHMBP2	NM_002180.3 linkuse as main transcript	c.1488C>A	p.Cys496*	stop_gained	10/15	ENST00000255078.8	NP_002171.2	P38935

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGHMBP2	ENST00000255078.8 linkuse as main transcript	c.1488C>A	p.Cys496*	stop_gained	10/15	1	NM_002180.3	ENSP00000255078.4		P38935

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.000158

AC:

AN:

233468

Hom.:

AF XY:

0.000166

AC XY:

AN XY:

126560

show subpopulations

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 SAS 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.:

Cov.:

AF XY:

0.000376

AC XY:

272

AN XY:

722552

show subpopulations

Gnomad4 AFR exome

AF:

0.0000599

Gnomad4 AMR exome

AF:

0.000161

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000113

Gnomad4 NFE exome

AF:

0.000460

Gnomad4 OTH exome

AF:

0.000267

GnomAD4 genome

AF:

0.000118

AC:

AN:

152256

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000252

Hom.:

Bravo

AF:

0.000117

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000148

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:19

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 26, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 07, 2024	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 16, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 02, 2017	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. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 15, 2024	PM2, PM3, PS4_moderate, PVS1 -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Autosomal recessive distal spinal muscular atrophy 1

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Sep 02, 2022	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 -
Pathogenic, criteria provided, single submitter	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	Aug 18, 2015	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

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

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	research	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	-	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 23, 2024	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. -

Charcot-Marie-Tooth disease

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

IGHMBP2-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 19, 2024

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 23, 2020

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

Pathogenic, criteria provided, single submitter

clinical testing

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

Jun 14, 2022

- -

Charcot-Marie-Tooth disease axonal type 2S

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Oct 24, 2018

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

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

DANN

Uncertain

0.98

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.35

Vest4

0.91

GERP RS

-5.5

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over