rs622082

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.2011A>G(p.Thr671Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.295 in 1,613,488 control chromosomes in the GnomAD database, including 74,641 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. T671R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.25 ( 5443 hom., cov: 33)

Exomes 𝑓: 0.30 ( 69198 hom. )

Consequence

IGHMBP2
NM_002180.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -1.58

Publications

64 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=2.5120378E-4).

BP6

Variant 11-68936491-A-G is Benign according to our data. Variant chr11-68936491-A-G is described in ClinVar as Benign. ClinVar VariationId is 258566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.439 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGHMBP2	NM_002180.3 link	c.2011A>G	p.Thr671Ala	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.2011A>G	p.Thr671Ala	missense_variant	Exon 13 of 15	1	NM_002180.3	ENSP00000255078.4		P38935

Frequencies

GnomAD3 genomes

AF:

0.250

AC:

37938

AN:

151982

Hom.:

5448

Cov.:

show subpopulations

Gnomad AFR

AF:

0.129

Gnomad AMI

AF:

0.152

Gnomad AMR

AF:

0.181

Gnomad ASJ

AF:

0.377

Gnomad EAS

AF:

0.198

Gnomad SAS

AF:

0.455

Gnomad FIN

AF:

0.365

Gnomad MID

AF:

0.358

Gnomad NFE

AF:

0.305

Gnomad OTH

AF:

0.239

GnomAD2 exomes

AF:

0.291

AC:

72856

AN:

250432

AF XY:

0.307

show subpopulations

Gnomad AFR exome

AF:

0.123

Gnomad AMR exome

AF:

0.129

Gnomad ASJ exome

AF:

0.368

Gnomad EAS exome

AF:

0.196

Gnomad FIN exome

AF:

0.379

Gnomad NFE exome

AF:

0.311

Gnomad OTH exome

AF:

0.296

GnomAD4 exome

AF:

0.300

AC:

438739

AN:

1461388

Hom.:

69198

Cov.:

AF XY:

0.308

AC XY:

223655

AN XY:

727002

show subpopulations

African (AFR)

AF:

0.120

AC:

4031

AN:

33480

American (AMR)

AF:

0.132

AC:

5910

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.364

AC:

9501

AN:

26134

East Asian (EAS)

AF:

0.215

AC:

8525

AN:

39700

South Asian (SAS)

AF:

0.456

AC:

39348

AN:

86254

European-Finnish (FIN)

AF:

0.377

AC:

19975

AN:

53038

Middle Eastern (MID)

AF:

0.351

AC:

2024

AN:

5768

European-Non Finnish (NFE)

AF:

0.298

AC:

331637

AN:

1111916

Other (OTH)

AF:

0.295

AC:

17788

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

19689

39379

59068

78758

98447

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10700

21400

32100

42800

53500

<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:

0.249

AC:

37933

AN:

152100

Hom.:

5443

Cov.:

AF XY:

0.254

AC XY:

18920

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.128

AC:

5335

AN:

41528

American (AMR)

AF:

0.180

AC:

2757

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.377

AC:

1309

AN:

3470

East Asian (EAS)

AF:

0.198

AC:

1018

AN:

5154

South Asian (SAS)

AF:

0.455

AC:

2192

AN:

4814

European-Finnish (FIN)

AF:

0.365

AC:

3866

AN:

10580

Middle Eastern (MID)

AF:

0.364

AC:

107

AN:

294

European-Non Finnish (NFE)

AF:

0.305

AC:

20710

AN:

67958

Other (OTH)

AF:

0.237

AC:

500

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1428

2857

4285

5714

7142

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

410

820

1230

1640

2050

<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:

0.287

Hom.:

21512

Bravo

AF:

0.225

TwinsUK

AF:

0.293

AC:

1086

ALSPAC

AF:

0.300

AC:

1155

ESP6500AA

AF:

0.127

AC:

559

ESP6500EA

AF:

0.308

AC:

2645

ExAC

AF:

0.298

AC:

36138

Asia WGS

AF:

0.302

AC:

1047

AN:

3478

EpiCase

AF:

0.303

EpiControl

AF:

0.310

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 03, 2021

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Nov 23, 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: 29083408, 32640185) -

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

Jan 13, 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

- -

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 03, 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

0.053

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.58

CADD

Benign

0.0060

(source)

DANN

Benign

0.24

DEOGEN2

Benign

0.080

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.13

MetaRNN

Benign

0.00025

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.49

PhyloP100

-1.6

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.27

REVEL

Benign

0.18

Sift

Benign

0.94

Sift4G

Benign

0.73

Polyphen

0.0

Vest4

0.0090

MPC

0.19

ClinPred

0.00067

GERP RS

-6.7

PromoterAI

-0.024

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.024

gMVP

0.25

Mutation Taster

=93/7

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