rs10896380

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.823A>G(p.Ile275Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.218 in 1,613,918 control chromosomes in the GnomAD database, including 41,567 homozygotes. 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 Benign (★★).

Frequency

Genomes: 𝑓 0.19 ( 3019 hom., cov: 32)

Exomes 𝑓: 0.22 ( 38548 hom. )

Consequence

IGHMBP2
NM_002180.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.47

Publications

37 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=0.0015553236).

BP6

Variant 11-68914934-A-G is Benign according to our data. Variant chr11-68914934-A-G is described in ClinVar as Benign. ClinVar VariationId is 258577.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.823A>G	p.Ile275Val	missense_variant	Exon 6 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.823A>G	p.Ile275Val	missense_variant	Exon 6 of 15	1	NM_002180.3	ENSP00000255078.4		P38935

Frequencies

GnomAD3 genomes

AF:

0.186

AC:

28361

AN:

152074

Hom.:

3017

Cov.:

show subpopulations

Gnomad AFR

AF:

0.120

Gnomad AMI

AF:

0.307

Gnomad AMR

AF:

0.204

Gnomad ASJ

AF:

0.280

Gnomad EAS

AF:

0.0236

Gnomad SAS

AF:

0.0606

Gnomad FIN

AF:

0.123

Gnomad MID

AF:

0.203

Gnomad NFE

AF:

0.246

Gnomad OTH

AF:

0.244

GnomAD2 exomes

AF:

0.182

AC:

45868

AN:

251462

AF XY:

0.182

show subpopulations

Gnomad AFR exome

AF:

0.124

Gnomad AMR exome

AF:

0.183

Gnomad ASJ exome

AF:

0.275

Gnomad EAS exome

AF:

0.0239

Gnomad FIN exome

AF:

0.132

Gnomad NFE exome

AF:

0.247

Gnomad OTH exome

AF:

0.215

GnomAD4 exome

AF:

0.222

AC:

323970

AN:

1461726

Hom.:

38548

Cov.:

AF XY:

0.217

AC XY:

158137

AN XY:

727210

show subpopulations

African (AFR)

AF:

0.119

AC:

3997

AN:

33478

American (AMR)

AF:

0.184

AC:

8239

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.278

AC:

7254

AN:

26136

East Asian (EAS)

AF:

0.0271

AC:

1075

AN:

39698

South Asian (SAS)

AF:

0.0699

AC:

6030

AN:

86254

European-Finnish (FIN)

AF:

0.133

AC:

7111

AN:

53418

Middle Eastern (MID)

AF:

0.220

AC:

1270

AN:

5768

European-Non Finnish (NFE)

AF:

0.248

AC:

276231

AN:

1111868

Other (OTH)

AF:

0.211

AC:

12763

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

14103

28206

42310

56413

70516

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9178

18356

27534

36712

45890

<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:

0.186

AC:

28372

AN:

152192

Hom.:

3019

Cov.:

AF XY:

0.179

AC XY:

13330

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.120

AC:

4996

AN:

41542

American (AMR)

AF:

0.203

AC:

3108

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.280

AC:

970

AN:

3468

East Asian (EAS)

AF:

0.0238

AC:

123

AN:

5166

South Asian (SAS)

AF:

0.0601

AC:

290

AN:

4828

European-Finnish (FIN)

AF:

0.123

AC:

1309

AN:

10602

Middle Eastern (MID)

AF:

0.201

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.246

AC:

16728

AN:

67996

Other (OTH)

AF:

0.241

AC:

509

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1133

2266

3400

4533

5666

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

296

592

888

1184

1480

<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:

0.231

Hom.:

16059

Bravo

AF:

0.194

TwinsUK

AF:

0.248

AC:

918

ALSPAC

AF:

0.244

AC:

942

ESP6500AA

AF:

0.124

AC:

545

ESP6500EA

AF:

0.248

AC:

2127

ExAC

AF:

0.182

AC:

22083

Asia WGS

AF:

0.0560

AC:

196

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:3

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: 18% of total chromosomes in ExAC -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Autosomal recessive distal spinal muscular atrophy 1

Benign:3

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

0.072

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.74

DEOGEN2

Benign

0.15

Eigen

Benign

-0.99

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.81

MetaRNN

Benign

0.0016

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.36

PhyloP100

1.5

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.23

REVEL

Benign

0.16

Sift

Benign

0.74

Sift4G

Benign

1.0

Polyphen

0.0030

Vest4

0.048

MPC

0.17

ClinPred

0.0019

GERP RS

0.050

PromoterAI

-0.010

Neutral

(source)

Varity_R

0.076

gMVP

0.31

Mutation Taster

=92/8

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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