chr11-68939671-T-G

Variant names:

• chr11-68939671-T-G
• rs147674615
• NM_002180.3:c.2922T>G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_002180.3(IGHMBP2):​c.2922T>G​(p.Asp974Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00189 in 1,612,916 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (4 hom.)
• Consequence: IGHMBP2 NM_002180.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:5 O:1
• Conservation: PhyloP100: -0.384
• Publications: 12 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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15927237).
• BP6: Variant 11-68939671-T-G is Benign according to our data. Variant chr11-68939671-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 194494.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0014 (213/152152) while in subpopulation NFE AF = 0.00234 (159/67984). AF 95% confidence interval is 0.00204. There are 1 homozygotes in GnomAd4. There are 96 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002180.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGHMBP2	NM_002180.3	MANE Select	c.2922T>G	p.Asp974Glu	missense	Exon 15 of 15	NP_002171.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGHMBP2	ENST00000255078.8	TSL:1 MANE Select	c.2922T>G	p.Asp974Glu	missense	Exon 15 of 15	ENSP00000255078.4
	IGHMBP2	ENST00000544521.1	TSL:1	n.753T>G		non_coding_transcript_exon	Exon 2 of 2
	IGHMBP2	ENST00000543739.5	TSL:2	n.1915T>G		non_coding_transcript_exon	Exon 6 of 6

Frequencies

GnomAD3 genomes AF: 0.00140 AC: 213 AN: 152034 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000749

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000378

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00234

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00104 AC: 257 AN: 247262 AF XY: 0.00106

Gnomad AFR exome AF: 0.000700

Gnomad AMR exome AF: 0.000758

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000945

Gnomad NFE exome AF: 0.00184

Gnomad OTH exome AF: 0.00201

GnomAD4 exome AF: 0.00195 AC: 2842 AN: 1460764 Hom.: 4 Cov.: 31 AF XY: 0.00185 AC XY: 1346 AN XY: 726662

African (AFR) AF: 0.000388 AC: 13 AN: 33470

American (AMR) AF: 0.000919 AC: 41 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26060

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86150

European-Finnish (FIN) AF: 0.000378 AC: 20 AN: 52966

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 0.00237 AC: 2630 AN: 1111782

Other (OTH) AF: 0.00209 AC: 126 AN: 60324

GnomAD4 genome AF: 0.00140 AC: 213 AN: 152152 Hom.: 1 Cov.: 33 AF XY: 0.00129 AC XY: 96 AN XY: 74376

African (AFR) AF: 0.000746 AC: 31 AN: 41530

American (AMR) AF: 0.00118 AC: 18 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.000378 AC: 4 AN: 10588

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

European-Non Finnish (NFE) AF: 0.00234 AC: 159 AN: 67984

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00180 Hom.: 0

Bravo AF: 0.00148

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.000964 AC: 117

EpiCase AF: 0.00207

EpiControl AF: 0.00155

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:5 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:2

Dec 01, 2014

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The IGHMBP2 p.Asp974Glu variant was identified 1 of 58 proband chromosomes (frequency: 0.017) from an infant with distal spinal muscular atrophy with respiratory distress type 1 (SMARD1) who carried another variant of uncertain significance in the IGHMBP2 gene (Grohmann_2003_PMID: 14681881). The variant was identified in dbSNP (ID: rs147674615) and ClinVar (classified as uncertain significance by Athena diagnostics, ARUP laboratories, EGL Diagnostics, and Illuminal, and as likely benign by Invitae). The variant was identified in control databases in 304 of 278604 chromosomes (1 homozygous) at a frequency of 0.001091 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 239 of 126884 chromosomes (freq: 0.001884), Other in 12 of 7070 chromosomes (freq: 0.001697), African in 21 of 24426 chromosomes (freq: 0.00086), Latino in 28 of 35132 chromosomes (freq: 0.000797), European (Finnish) in 3 of 24636 chromosomes (freq: 0.000122) and South Asian in 1 of 30452 chromosomes (freq: 0.000033), but was not observed in the Ashkenazi Jewish or East Asian populations. The p.Asp974 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

Apr 15, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

IGHMBP2: BS1

Oct 13, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The IGHMBP2 c.2922T>G; p.Asp974Glu variant (rs147674615) is reported in the literature in individuals with respiratory distress and/or sudden death (Grohmann 2003, Salfati 2019, Torkamani 2016), and in large cohorts of individuals with Charcot-Marie-Tooth disease or peripheral neuropathy (Antoniadi 2015, Volodarsky 2021). This variant is also reported in ClinVar (Variation ID: 194494), and is found in the general population with an overall allele frequency of 0.11% (304/278604 alleles, including a single homozygote) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.664). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Antoniadi T et al. Application of targeted multi-gene panel testing for the diagnosis of inherited peripheral neuropathy provides a high diagnostic yield with unexpected phenotype-genotype variability. BMC Med Genet. 2015 Sep 21;16:84. PMID: 26392352. Grohmann et al. Infantile spinal muscular atrophy with respiratory distress type 1 (SMARD1). Ann Neurol. 2003 Dec;54(6):719-24. PMID: 14681881. Salfati EL et al. Re-analysis of whole-exome sequencing data uncovers novel diagnostic variants and improves molecular diagnostic yields for sudden death and idiopathic diseases. Genome Med. 2019 Dec 17;11(1):83. PMID: 31847883. Torkamani A et al. Molecular Autopsy for Sudden Unexpected Death. JAMA. 2016 Oct 11;316(14):1492-1494. PMID: 27727376. Volodarsky M et al. Comprehensive genetic sequence and copy number analysis for Charcot-Marie-Tooth disease in a Canadian cohort of 2517 patients. J Med Genet. 2021 Apr;58(4):284-288. PMID: 32376792.

not specified Benign:2

Mar 10, 2025

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: IGHMBP2 c.2922T>G (p.Asp974Glu) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0019 in 1612916 control chromosomes, predominantly at a frequency of 0.0024 within the Non-Finnish European subpopulation in the gnomAD database, including 5 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2.2-fold of the estimated maximal expected allele frequency for a pathogenic variant in IGHMBP2 causing Charcot-Marie-Tooth disease axonal type 2S phenotype (0.0011). c.2922T>G has been reported in the literature in at least an individual affected with IGHMBP2-related conditions (Grohmann_2003) . These report(s) do not provide unequivocal conclusions about association of the variant with Charcot-Marie-Tooth disease axonal type 2S. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 14681881). ClinVar contains an entry for this variant (Variation ID: 194494). Based on the evidence outlined above, the variant was classified as likely benign.

Apr 02, 2020

Athena Diagnostics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Charcot-Marie-Tooth disease Uncertain:1

Molecular Genetics Laboratory, London Health Sciences Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Inborn genetic diseases Uncertain:1

Nov 27, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2922T>G (p.D974E) alteration is located in exon 15 (coding exon 15) of the IGHMBP2 gene. This alteration results from a T to G substitution at nucleotide position 2922, causing the aspartic acid (D) at amino acid position 974 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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

Jul 11, 2018

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

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

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal recessive distal spinal muscular atrophy 1 Other:1

Genomeconnect - The Bow Foundation (GNAO1)

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant classified as Uncertain significance and reported on 11-26-2014 by UCLA Molecular Diagnostics Laboratories. GenomeConnect-GNAO1 Registry assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.030
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Benign	0.00052
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.16	T
MetaSVM	Uncertain	0.38	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		-0.38
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.7	N
REVEL	Pathogenic	0.66
Sift	Benign	0.034	D
Sift4G	Benign	0.29	T
Polyphen		1.0	D
Vest4		0.72
MVP		0.90
MPC		0.24
ClinPred		0.047	T
GERP RS		-1.0
Varity_R		0.17
gMVP		0.30
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs147674615; hg19: chr11-68707139; COSMIC: COSV54825330; COSMIC: COSV54825330;