11-68936560-C-T

Position:

chr11-68936560-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002180.3(IGHMBP2):c.2080C>T(p.Arg694Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.221 in 1,611,560 control chromosomes in the GnomAD database, including 42,150 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R694Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.20 ( 3353 hom., cov: 33)

Exomes 𝑓: 0.22 ( 38797 hom. )

Consequence

IGHMBP2
NM_002180.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.319

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005527556).

BP6

Variant 11-68936560-C-T is Benign according to our data. Variant chr11-68936560-C-T is described in ClinVar as [Benign]. Clinvar id is 258567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68936560-C-T is described in Lovd as [Benign].

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/exons	MANE	UniProt
IGHMBP2	NM_002180.3 linkuse as main transcript	c.2080C>T	p.Arg694Trp	missense_variant	13/15	ENST00000255078.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGHMBP2	ENST00000255078.8 linkuse as main transcript	c.2080C>T	p.Arg694Trp	missense_variant	13/15	1	NM_002180.3	P1

Frequencies

GnomAD3 genomes

AF:

0.201

AC:

30599

AN:

152002

Hom.:

3352

Cov.:

show subpopulations

Gnomad AFR

AF:

0.170

Gnomad AMI

AF:

0.307

Gnomad AMR

AF:

0.209

Gnomad ASJ

AF:

0.280

Gnomad EAS

AF:

0.0297

Gnomad SAS

AF:

0.0678

Gnomad FIN

AF:

0.124

Gnomad MID

AF:

0.203

Gnomad NFE

AF:

0.246

Gnomad OTH

AF:

0.255

GnomAD3 exomes

AF:

0.188

AC:

46754

AN:

249024

Hom.:

5077

AF XY:

0.187

AC XY:

25173

AN XY:

134922

show subpopulations

Gnomad AFR exome

AF:

0.179

Gnomad AMR exome

AF:

0.185

Gnomad ASJ exome

AF:

0.276

Gnomad EAS exome

AF:

0.0294

Gnomad SAS exome

AF:

0.0762

Gnomad FIN exome

AF:

0.132

Gnomad NFE exome

AF:

0.247

Gnomad OTH exome

AF:

0.219

GnomAD4 exome

AF:

0.224

AC:

326345

AN:

1459440

Hom.:

38797

Cov.:

AF XY:

0.219

AC XY:

159223

AN XY:

725868

show subpopulations

Gnomad4 AFR exome

AF:

0.174

Gnomad4 AMR exome

AF:

0.186

Gnomad4 ASJ exome

AF:

0.278

Gnomad4 EAS exome

AF:

0.0308

Gnomad4 SAS exome

AF:

0.0782

Gnomad4 FIN exome

AF:

0.134

Gnomad4 NFE exome

AF:

0.248

Gnomad4 OTH exome

AF:

0.216

GnomAD4 genome

AF:

0.201

AC:

30602

AN:

152120

Hom.:

3353

Cov.:

AF XY:

0.194

AC XY:

14419

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.170

Gnomad4 AMR

AF:

0.209

Gnomad4 ASJ

AF:

0.280

Gnomad4 EAS

AF:

0.0298

Gnomad4 SAS

AF:

0.0672

Gnomad4 FIN

AF:

0.124

Gnomad4 NFE

AF:

0.246

Gnomad4 OTH

AF:

0.252

Alfa

AF:

0.235

Hom.:

9283

Bravo

AF:

0.211

TwinsUK

AF:

0.248

AC:

921

ALSPAC

AF:

0.245

AC:

945

ESP6500AA

AF:

0.174

AC:

766

ESP6500EA

AF:

0.248

AC:

2129

ExAC

AF:

0.188

AC:

22756

Asia WGS

AF:

0.0700

AC:

248

AN:

3478

EpiCase

AF:

0.249

EpiControl

AF:

0.255

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	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: 19% of total chromosomes in ExAC -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 17, 2015	- -

Autosomal recessive distal spinal muscular atrophy 1

Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 14, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -

Charcot-Marie-Tooth disease

Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Charcot-Marie-Tooth disease axonal type 2S

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.41

MetaRNN

Benign

0.0055

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.2

MutationTaster

Benign

1.0

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.19

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.060

Polyphen

0.013

Vest4

0.047

MPC

0.20

ClinPred

0.038

GERP RS

3.5

Varity_R

0.071

gMVP

0.34

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