rs622082

Variant summary

Our verdict is Benign. Variant got -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. 15/20 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. T671M) 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:11

Conservation

PhyloP100: -1.58

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 258566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68936491-A-G is described in Lovd as [Benign].

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/exons	MANE	UniProt
IGHMBP2	NM_002180.3 linkuse as main transcript	c.2011A>G	p.Thr671Ala	missense_variant	13/15	ENST00000255078.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGHMBP2	ENST00000255078.8 linkuse as main transcript	c.2011A>G	p.Thr671Ala	missense_variant	13/15	1	NM_002180.3	P1

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

GnomAD3 exomes

AF:

0.291

AC:

72856

AN:

250432

Hom.:

12000

AF XY:

0.307

AC XY:

41619

AN XY:

135510

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 SAS exome

AF:

0.456

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

Gnomad4 AFR exome

AF:

0.120

Gnomad4 AMR exome

AF:

0.132

Gnomad4 ASJ exome

AF:

0.364

Gnomad4 EAS exome

AF:

0.215

Gnomad4 SAS exome

AF:

0.456

Gnomad4 FIN exome

AF:

0.377

Gnomad4 NFE exome

AF:

0.298

Gnomad4 OTH exome

AF:

0.295

GnomAD4 genome

AF:

0.249

AC:

37933

AN:

152100

Hom.:

5443

Cov.:

AF XY:

0.254

AC XY:

18920

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.128

Gnomad4 AMR

AF:

0.180

Gnomad4 ASJ

AF:

0.377

Gnomad4 EAS

AF:

0.198

Gnomad4 SAS

AF:

0.455

Gnomad4 FIN

AF:

0.365

Gnomad4 NFE

AF:

0.305

Gnomad4 OTH

AF:

0.237

Alfa

AF:

0.297

Hom.:

14634

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:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Autosomal recessive distal spinal muscular atrophy 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 29083408, 32640185) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Charcot-Marie-Tooth disease

Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

Autosomal recessive distal spinal muscular atrophy 1;C4015349:Charcot-Marie-Tooth disease axonal type 2S

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Charcot-Marie-Tooth disease axonal type 2S

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

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

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

MutationTaster

Benign

1.0

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

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.024

gMVP

0.25

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over