rs149824485

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_002180.3(IGHMBP2):c.2837G>A(p.Arg946Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000802 in 1,613,084 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R946W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00078 ( 1 hom. )

Consequence

IGHMBP2
NM_002180.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:4

Conservation

PhyloP100: 2.88

Publications

4 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008040965).

BP6

Variant 11-68939586-G-A is Benign according to our data. Variant chr11-68939586-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 246570.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00102 (156/152244) while in subpopulation NFE AF = 0.00125 (85/68038). AF 95% confidence interval is 0.00103. There are 0 homozygotes in GnomAd4. There are 74 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGHMBP2	NM_002180.3 link	c.2837G>A	p.Arg946Gln	missense_variant	Exon 15 of 15	ENST00000255078.8	NP_002171.2	P38935
IGHMBP2	XM_017017670.3 link	c.1826G>A	p.Arg609Gln	missense_variant	Exon 11 of 11		XP_016873159.1
IGHMBP2	XM_005273975.4 link	c.1709G>A	p.Arg570Gln	missense_variant	Exon 8 of 8		XP_005274032.1
IGHMBP2	XM_011544994.2 link	c.1604G>A	p.Arg535Gln	missense_variant	Exon 8 of 8		XP_011543296.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGHMBP2	ENST00000255078.8 link	c.2837G>A	p.Arg946Gln	missense_variant	Exon 15 of 15	1	NM_002180.3	ENSP00000255078.4		P38935

Frequencies

GnomAD3 genomes

AF:

0.00102

AC:

156

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.0603

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00125

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000623

AC:

156

AN:

250540

AF XY:

0.000663

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00122

Gnomad OTH exome

AF:

0.000819

GnomAD4 exome

AF:

0.000778

AC:

1137

AN:

1460840

Hom.:

Cov.:

AF XY:

0.000744

AC XY:

541

AN XY:

726714

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33466

American (AMR)

AF:

0.000447

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86230

European-Finnish (FIN)

AF:

0.0000189

AC:

AN:

52980

Middle Eastern (MID)

AF:

0.000377

AC:

AN:

5300

European-Non Finnish (NFE)

AF:

0.000964

AC:

1072

AN:

1111984

Other (OTH)

AF:

0.000547

AC:

AN:

60334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

136

203

271

339

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

176

220

<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:

0.00102

AC:

156

AN:

152244

Hom.:

Cov.:

AF XY:

0.000995

AC XY:

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41468

American (AMR)

AF:

0.000458

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00125

AC:

AN:

68038

Other (OTH)

AF:

0.000479

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000934

Hom.:

Bravo

AF:

0.00136

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000659

AC:

EpiCase

AF:

0.00174

EpiControl

AF:

0.00202

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:2

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

IGHMBP2: BP4 -

Nov 28, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported in a single individual with CMT and classified as a variant of uncertain signficance by the authors; no information about patient phenotype or segregation was provided (Volodarsky et al., 2021); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32376792) -

Feb 27, 2019

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 12, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The IGHMBP2 c.2837G>A; p.Arg946Gln variant (rs149824485) is reported in a cohort of Charcot-Marie-Tooth disease (Volodarsky 2021). This variant is also reported in ClinVar (Variation ID: 246570). This variant is observed in the general population with an overall allele frequency of 0.06% (183/281926 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is neutral (REVEL: 0.089). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Volodarsky M et al. Comprehensive genetic sequence and copy number analysis for Charcot-Marie-Tooth disease in a Canadian cohort of 2517 patients. J Med Genet. 2021 Apr;58(4):284-288. PMID: 32376792. -

Oct 31, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BP4 -

Mar 06, 2020

Revvity Omics, Revvity

Significance:Uncertain significance

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

Uncertain:1Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 01, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Charcot-Marie-Tooth disease

Uncertain:1

Molecular Genetics Laboratory, London Health Sciences Centre

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Oct 05, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2837G>A (p.R946Q) alteration is located in exon 15 (coding exon 15) of the IGHMBP2 gene. This alteration results from a G to A substitution at nucleotide position 2837, causing the arginine (R) at amino acid position 946 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Autosomal recessive distal spinal muscular atrophy 1

Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified

Benign:1

Dec 10, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: IGHMBP2 c.2837G>A (p.Arg946Gln) results in a conservative amino acid change located in the AN1-like Zinc finger (IPR000058) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00062 in 250540 control chromosomes, predominantly at a frequency of 0.0012 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.073 fold of the estimated maximal expected allele frequency for a pathogenic variant in IGHMBP2 causing Charcot-Marie-Tooth disease axonal type 2S phenotype (0.0011). To our knowledge, no occurrence of c.2837G>A in individuals affected with Charcot-Marie-Tooth disease axonal type 2S and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 246570). Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.13

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.026

MetaRNN

Benign

0.0080

MetaSVM

Benign

-0.90

MutationAssessor

Uncertain

2.3

PhyloP100

2.9

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.4

REVEL

Benign

0.089

Sift

Uncertain

0.0090

Sift4G

Benign

0.25

Polyphen

0.98

Vest4

0.15

MVP

0.49

MPC

0.65

ClinPred

0.075

GERP RS

4.5

Varity_R

0.13

gMVP

0.25

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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