Genetic Variant IGHMBP2:p.Val518Val (chr11-68934480-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_002180.3(IGHMBP2):c.1554C>T(p.Val518Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.221 in 1,608,376 control chromosomes in the GnomAD database, including 41,992 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.20 ( 3352 hom., cov: 33)

Exomes 𝑓: 0.22 ( 38640 hom. )

Consequence

IGHMBP2
NM_002180.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.877

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.61).

BP6

Variant 11-68934480-C-T is Benign according to our data. Variant chr11-68934480-C-T is described in ClinVar as [Benign]. Clinvar id is 258560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68934480-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.877 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.243 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGHMBP2	NM_002180.3 link	c.1554C>T	p.Val518Val	synonymous_variant	Exon 11 of 15	ENST00000255078.8	NP_002171.2	P38935

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGHMBP2	ENST00000255078.8 link	c.1554C>T	p.Val518Val	synonymous_variant	Exon 11 of 15	1	NM_002180.3	ENSP00000255078.4		P38935

Frequencies

GnomAD3 genomes

AF:

0.201

AC:

30606

AN:

152126

Hom.:

3350

Cov.:

show subpopulations

Gnomad AFR

AF:

0.170

Gnomad AMI

AF:

0.307

Gnomad AMR

AF:

0.208

Gnomad ASJ

AF:

0.280

Gnomad EAS

AF:

0.0300

Gnomad SAS

AF:

0.0675

Gnomad FIN

AF:

0.124

Gnomad MID

AF:

0.203

Gnomad NFE

AF:

0.246

Gnomad OTH

AF:

0.255

GnomAD3 exomes

AF:

0.186

AC:

45258

AN:

243508

Hom.:

4805

AF XY:

0.185

AC XY:

24327

AN XY:

131736

show subpopulations

Gnomad AFR exome

AF:

0.177

Gnomad AMR exome

AF:

0.184

Gnomad ASJ exome

AF:

0.274

Gnomad EAS exome

AF:

0.0291

Gnomad SAS exome

AF:

0.0756

Gnomad FIN exome

AF:

0.130

Gnomad NFE exome

AF:

0.245

Gnomad OTH exome

AF:

0.219

GnomAD4 exome

AF:

0.223

AC:

324909

AN:

1456132

Hom.:

38640

Cov.:

AF XY:

0.219

AC XY:

158478

AN XY:

723986

show subpopulations

Gnomad4 AFR exome

AF:

0.173

Gnomad4 AMR exome

AF:

0.185

Gnomad4 ASJ exome

AF:

0.277

Gnomad4 EAS exome

AF:

0.0308

Gnomad4 SAS exome

AF:

0.0779

Gnomad4 FIN exome

AF:

0.133

Gnomad4 NFE exome

AF:

0.248

Gnomad4 OTH exome

AF:

0.216

GnomAD4 genome

AF:

0.201

AC:

30618

AN:

152244

Hom.:

3352

Cov.:

AF XY:

0.194

AC XY:

14425

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.170

Gnomad4 AMR

AF:

0.208

Gnomad4 ASJ

AF:

0.280

Gnomad4 EAS

AF:

0.0301

Gnomad4 SAS

AF:

0.0669

Gnomad4 FIN

AF:

0.124

Gnomad4 NFE

AF:

0.246

Gnomad4 OTH

AF:

0.252

Alfa

AF:

0.234

Hom.:

2422

Bravo

AF:

0.211

Asia WGS

AF:

0.0700

AC:

248

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 23% of total chromosomes in ExAC -

Autosomal recessive distal spinal muscular atrophy 1

Benign:3

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 14, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

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

- -

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

- -

Charcot-Marie-Tooth disease axonal type 2S

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.61

CADD

Benign

3.8

DANN

Benign

0.90

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

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