11-68936560-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. 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:12

Conservation

PhyloP100: 0.319

Publications

30 publications found

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 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

IGHMBP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 258567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.2080C>T	p.Arg694Trp	missense_variant	Exon 13 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.2080C>T	p.Arg694Trp	missense_variant	Exon 13 of 15	1	NM_002180.3	ENSP00000255078.4		P38935

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

GnomAD2 exomes

AF:

0.188

AC:

46754

AN:

249024

AF XY:

0.187

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 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

African (AFR)

AF:

0.174

AC:

5802

AN:

33386

American (AMR)

AF:

0.186

AC:

8291

AN:

44598

Ashkenazi Jewish (ASJ)

AF:

0.278

AC:

7242

AN:

26076

East Asian (EAS)

AF:

0.0308

AC:

1223

AN:

39682

South Asian (SAS)

AF:

0.0782

AC:

6742

AN:

86216

European-Finnish (FIN)

AF:

0.134

AC:

7028

AN:

52644

Middle Eastern (MID)

AF:

0.223

AC:

1284

AN:

5762

European-Non Finnish (NFE)

AF:

0.248

AC:

275690

AN:

1110778

Other (OTH)

AF:

0.216

AC:

13043

AN:

60298

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

15088

30177

45265

60354

75442

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9212

18424

27636

36848

46060

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.201

AC:

30602

AN:

152120

Hom.:

3353

Cov.:

AF XY:

0.194

AC XY:

14419

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.170

AC:

7055

AN:

41492

American (AMR)

AF:

0.209

AC:

3189

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.280

AC:

972

AN:

3466

East Asian (EAS)

AF:

0.0298

AC:

154

AN:

5174

South Asian (SAS)

AF:

0.0672

AC:

324

AN:

4822

European-Finnish (FIN)

AF:

0.124

AC:

1319

AN:

10600

Middle Eastern (MID)

AF:

0.201

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.246

AC:

16718

AN:

67962

Other (OTH)

AF:

0.252

AC:

532

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1243

2486

3730

4973

6216

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

316

632

948

1264

1580

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.230

Hom.:

17714

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:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Jul 17, 2015

Eurofins Ntd Llc (ga)

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: 19% of total chromosomes in ExAC -

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

- -

Autosomal recessive distal spinal muscular atrophy 1

Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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. -

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

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

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

PhyloP100

0.32

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

PromoterAI

-0.20

Neutral

(source)

Varity_R

0.071

gMVP

0.34

Mutation Taster

=89/11

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over