rs143986510

Positions:

chr11-68936656-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_002180.3(IGHMBP2):c.2176G>A(p.Val726Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00078 in 1,613,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00081 ( 0 hom. )

Consequence

IGHMBP2
NM_002180.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:2

Conservation

PhyloP100: 0.204

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 Benign. Variant got -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.023467839).

BP6

Variant 11-68936656-G-A is Benign according to our data. Variant chr11-68936656-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 245631.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=7}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000466 (71/152350) while in subpopulation NFE AF= 0.000764 (52/68034). AF 95% confidence interval is 0.000598. There are 0 homozygotes in gnomad4. There are 29 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGHMBP2	NM_002180.3 linkuse as main transcript	c.2176G>A	p.Val726Met	missense_variant	13/15	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.2176G>A	p.Val726Met	missense_variant	13/15	1	NM_002180.3	ENSP00000255078.4		P38935

Frequencies

GnomAD3 genomes

AF:

0.000466

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000764

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000499

AC:

125

AN:

250696

Hom.:

AF XY:

0.000531

AC XY:

AN XY:

135630

show subpopulations

Gnomad AFR exome

AF:

0.000309

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000688

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000813

AC:

1188

AN:

1461606

Hom.:

Cov.:

AF XY:

0.000802

AC XY:

583

AN XY:

727106

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.000268

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000928

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.000933

Gnomad4 OTH exome

AF:

0.000778

GnomAD4 genome

AF:

0.000466

AC:

AN:

152350

Hom.:

Cov.:

AF XY:

0.000389

AC XY:

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.000192

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000764

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000728

Hom.:

Bravo

AF:

0.000540

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.000699

AC:

ExAC

AF:

0.000428

AC:

EpiCase

AF:

0.000818

EpiControl

AF:

0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:6

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 17, 2021	The IGHMBP2 c.2176G>A; p.Val726Met variant (rs143986510) is reported in the literature in an individual affected with amyotrophic lateral sclerosis along with a pathogenic SQSTM1 variant (Pensato 2020), and an individual affected with congenital hypomyelinating neuropathy along with a de novo likely pathogenic SETX variant (Blake 2020). This variant is also reported in ClinVar (Variation ID: 245631). This variant is found in the South Asian population with an allele frequency of 0.098% (30/30606 alleles). The valine at codon 726 is weakly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.18). Due to limited information, the clinical significance of this variant is uncertain at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	IGHMBP2: PM2, BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 25, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 19, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 29, 2020	Has been observed in the heterozygous state in a patient with amyotrophic lateral sclerosis in the published literature; this individual also harbored a variant in the SQSTM1 gene (Pensato et al., 2020); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32028661) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 03, 2016	- -

Autosomal recessive distal spinal muscular atrophy 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 22, 2021

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 08, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.37

CADD

Benign

0.35

DANN

Benign

0.65

DEOGEN2

Benign

0.082

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.31

M_CAP

Benign

0.038

MetaRNN

Benign

0.023

MetaSVM

Benign

-0.57

MutationAssessor

Benign

1.4

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.18

REVEL

Benign

0.18

Sift

Benign

0.26

Sift4G

Benign

0.24

Polyphen

0.0010

Vest4

0.12

MVP

0.57

MPC

0.19

ClinPred

0.0053

GERP RS

-1.2

Varity_R

0.026

gMVP

0.19

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