rs76707931

Variant names:

• chr11-68914852-C-T
• rs76707931
• NM_002180.3:c.741C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002180.3(IGHMBP2):​c.741C>T​(p.Ala247Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00662 in 1,614,250 control chromosomes in the GnomAD database, including 80 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0067 (74 hom.)
• Consequence: IGHMBP2 NM_002180.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -7.86
• Publications: 5 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BP6: Variant 11-68914852-C-T is Benign according to our data. Variant chr11-68914852-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 198145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-7.86 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00549 (837/152360) while in subpopulation AMR AF = 0.00896 (137/15298). AF 95% confidence interval is 0.00773. There are 6 homozygotes in GnomAd4. There are 411 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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.741C>T	p.Ala247Ala	synonymous	Exon 6 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.741C>T	p.Ala247Ala	synonymous	Exon 6 of 15	ENSP00000255078.4
	IGHMBP2	ENST00000675615.1		c.741C>T	p.Ala247Ala	synonymous	Exon 6 of 14	ENSP00000502413.1
	IGHMBP2	ENST00000675464.1		c.30C>T	p.Ala10Ala	synonymous	Exon 1 of 2	ENSP00000502650.1

Frequencies

GnomAD3 genomes AF: 0.00544 AC: 828 AN: 152242 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00903

Gnomad ASJ AF: 0.0133

Gnomad EAS AF: 0.00365

Gnomad SAS AF: 0.00745

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00716

Gnomad OTH AF: 0.00956

GnomAD2 exomes AF: 0.00682 AC: 1715 AN: 251362 AF XY: 0.00722

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00705

Gnomad ASJ exome AF: 0.0187

Gnomad EAS exome AF: 0.00375

Gnomad FIN exome AF: 0.00296

Gnomad NFE exome AF: 0.00766

Gnomad OTH exome AF: 0.0101

GnomAD4 exome AF: 0.00674 AC: 9854 AN: 1461890 Hom.: 74 Cov.: 32 AF XY: 0.00683 AC XY: 4965 AN XY: 727244

African (AFR) AF: 0.000866 AC: 29 AN: 33480

American (AMR) AF: 0.00689 AC: 308 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0182 AC: 475 AN: 26134

East Asian (EAS) AF: 0.00244 AC: 97 AN: 39700

South Asian (SAS) AF: 0.00687 AC: 593 AN: 86258

European-Finnish (FIN) AF: 0.00277 AC: 148 AN: 53420

Middle Eastern (MID) AF: 0.0267 AC: 154 AN: 5768

European-Non Finnish (NFE) AF: 0.00680 AC: 7562 AN: 1112010

Other (OTH) AF: 0.00808 AC: 488 AN: 60396

GnomAD4 genome AF: 0.00549 AC: 837 AN: 152360 Hom.: 6 Cov.: 33 AF XY: 0.00552 AC XY: 411 AN XY: 74506

African (AFR) AF: 0.00135 AC: 56 AN: 41588

American (AMR) AF: 0.00896 AC: 137 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0133 AC: 46 AN: 3470

East Asian (EAS) AF: 0.00366 AC: 19 AN: 5188

South Asian (SAS) AF: 0.00745 AC: 36 AN: 4830

European-Finnish (FIN) AF: 0.00235 AC: 25 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00719 AC: 489 AN: 68042

Other (OTH) AF: 0.0132 AC: 28 AN: 2114

Alfa AF: 0.00597 Hom.: 3

Bravo AF: 0.00556

Asia WGS AF: 0.0130 AC: 44 AN: 3478

EpiCase AF: 0.00900

EpiControl AF: 0.00966

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 08, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 29, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

IGHMBP2: BP4, BP7, BS2

not specified Benign:2

Nov 14, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Charcot-Marie-Tooth disease Benign:1

Molecular Genetics Laboratory, London Health Sciences Centre

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Inborn genetic diseases Benign:1

Jul 11, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal recessive distal spinal muscular atrophy 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	1.8
DANN	Benign	0.65
PhyloP100		-7.9
PromoterAI		0.0059	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=89/11	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: rs76707931; hg19: chr11-68682320;