rs10896380

Variant summary

Our verdict is Benign. Variant got -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. 15/20 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:10

Conservation

PhyloP100: 1.47

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=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 id is 258577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68914934-A-G is described in Lovd as [Benign].

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/exons	MANE	UniProt
IGHMBP2	NM_002180.3 linkuse as main transcript	c.823A>G	p.Ile275Val	missense_variant	6/15	ENST00000255078.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGHMBP2	ENST00000255078.8 linkuse as main transcript	c.823A>G	p.Ile275Val	missense_variant	6/15	1	NM_002180.3	P1

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

GnomAD3 exomes

AF:

0.182

AC:

45868

AN:

251462

Hom.:

4984

AF XY:

0.182

AC XY:

24771

AN XY:

135910

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 SAS exome

AF:

0.0670

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

Gnomad4 AFR exome

AF:

0.119

Gnomad4 AMR exome

AF:

0.184

Gnomad4 ASJ exome

AF:

0.278

Gnomad4 EAS exome

AF:

0.0271

Gnomad4 SAS exome

AF:

0.0699

Gnomad4 FIN exome

AF:

0.133

Gnomad4 NFE exome

AF:

0.248

Gnomad4 OTH exome

AF:

0.211

GnomAD4 genome

AF:

0.186

AC:

28372

AN:

152192

Hom.:

3019

Cov.:

AF XY:

0.179

AC XY:

13330

AN XY:

74414

show subpopulations

Gnomad4 AFR

AF:

0.120

Gnomad4 AMR

AF:

0.203

Gnomad4 ASJ

AF:

0.280

Gnomad4 EAS

AF:

0.0238

Gnomad4 SAS

AF:

0.0601

Gnomad4 FIN

AF:

0.123

Gnomad4 NFE

AF:

0.246

Gnomad4 OTH

AF:

0.241

Alfa

AF:

0.238

Hom.:

8341

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:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	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 -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Autosomal recessive distal spinal muscular atrophy 1

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 14, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	-	- -

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

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

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

0.072

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.46

Cadd

Benign

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

MutationTaster

Benign

0.11

P;P

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

Varity_R

0.076

gMVP

0.31

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