rs17612126

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.2636C>A(p.Thr879Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.272 in 1,613,734 control chromosomes in the GnomAD database, including 63,713 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T879M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.23 ( 4935 hom., cov: 32)

Exomes 𝑓: 0.28 ( 58778 hom. )

Consequence

IGHMBP2
NM_002180.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:13

Conservation

PhyloP100: -0.292

Publications

43 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=3.3271313E-4).

BP6

Variant 11-68938206-C-A is Benign according to our data. Variant chr11-68938206-C-A is described in ClinVar as Benign. ClinVar VariationId is 194368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.39 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGHMBP2	NM_002180.3 link	c.2636C>A	p.Thr879Lys	missense_variant	Exon 14 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.2636C>A	p.Thr879Lys	missense_variant	Exon 14 of 15	1	NM_002180.3	ENSP00000255078.4		P38935

Frequencies

GnomAD3 genomes

AF:

0.225

AC:

34238

AN:

152000

Hom.:

4928

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0649

Gnomad AMI

AF:

0.449

Gnomad AMR

AF:

0.397

Gnomad ASJ

AF:

0.125

Gnomad EAS

AF:

0.245

Gnomad SAS

AF:

0.177

Gnomad FIN

AF:

0.265

Gnomad MID

AF:

0.206

Gnomad NFE

AF:

0.282

Gnomad OTH

AF:

0.219

GnomAD2 exomes

AF:

0.264

AC:

66271

AN:

251418

AF XY:

0.256

show subpopulations

Gnomad AFR exome

AF:

0.0622

Gnomad AMR exome

AF:

0.464

Gnomad ASJ exome

AF:

0.135

Gnomad EAS exome

AF:

0.245

Gnomad FIN exome

AF:

0.247

Gnomad NFE exome

AF:

0.272

Gnomad OTH exome

AF:

0.257

GnomAD4 exome

AF:

0.277

AC:

404789

AN:

1461616

Hom.:

58778

Cov.:

AF XY:

0.273

AC XY:

198447

AN XY:

727156

show subpopulations

African (AFR)

AF:

0.0517

AC:

1732

AN:

33478

American (AMR)

AF:

0.457

AC:

20435

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.138

AC:

3601

AN:

26136

East Asian (EAS)

AF:

0.255

AC:

10105

AN:

39700

South Asian (SAS)

AF:

0.183

AC:

15764

AN:

86254

European-Finnish (FIN)

AF:

0.246

AC:

13085

AN:

53288

Middle Eastern (MID)

AF:

0.205

AC:

1180

AN:

5760

European-Non Finnish (NFE)

AF:

0.291

AC:

324000

AN:

1111896

Other (OTH)

AF:

0.247

AC:

14887

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

16134

32267

48401

64534

80668

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10788

21576

32364

43152

53940

<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:

0.225

AC:

34253

AN:

152118

Hom.:

4935

Cov.:

AF XY:

0.228

AC XY:

16948

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.0648

AC:

2690

AN:

41512

American (AMR)

AF:

0.398

AC:

6078

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.125

AC:

433

AN:

3468

East Asian (EAS)

AF:

0.245

AC:

1264

AN:

5158

South Asian (SAS)

AF:

0.177

AC:

856

AN:

4830

European-Finnish (FIN)

AF:

0.265

AC:

2800

AN:

10578

Middle Eastern (MID)

AF:

0.197

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.282

AC:

19205

AN:

67986

Other (OTH)

AF:

0.218

AC:

460

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1280

2560

3841

5121

6401

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

358

716

1074

1432

1790

<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:

0.252

Hom.:

14826

Bravo

AF:

0.231

TwinsUK

AF:

0.297

AC:

1100

ALSPAC

AF:

0.303

AC:

1169

ESP6500AA

AF:

0.0777

AC:

342

ESP6500EA

AF:

0.278

AC:

2387

ExAC

AF:

0.250

AC:

30305

Asia WGS

AF:

0.197

AC:

684

AN:

3478

EpiCase

AF:

0.280

EpiControl

AF:

0.270

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 13, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

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: 25% of total chromosomes in ExAC -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 24022109, 11528396, 20981092, 20220177, 16458836, 21228398, 15797190) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Autosomal recessive distal spinal muscular atrophy 1

Benign:2

Mar 06, 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. -

Apr 30, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Neuronopathy, distal hereditary motor, autosomal dominant

Uncertain:1

Inherited Neuropathy Consortium

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

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

0.086

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.49

CADD

Benign

0.24

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.060

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.47

MetaRNN

Benign

0.00033

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.2

PhyloP100

-0.29

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.24

REVEL

Benign

0.21

Sift

Benign

0.90

Sift4G

Benign

1.0

Polyphen

0.21

Vest4

0.050

MPC

0.23

ClinPred

0.0042

GERP RS

-3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.062

gMVP

0.20

Mutation Taster

=97/3

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