11-68911494-T-C

Position:

chr11-68911494-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002180.3(IGHMBP2):c.602T>C(p.Leu201Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.813 in 1,613,828 control chromosomes in the GnomAD database, including 538,558 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 0.76 ( 45193 hom., cov: 31)

Exomes 𝑓: 0.82 ( 493365 hom. )

Consequence

IGHMBP2
NM_002180.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0320

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=6.9917377E-7).

BP6

Variant 11-68911494-T-C is Benign according to our data. Variant chr11-68911494-T-C is described in ClinVar as [Benign]. Clinvar id is 258576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68911494-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.837 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGHMBP2	NM_002180.3 link	c.602T>C	p.Leu201Ser	missense_variant	5/15	ENST00000255078.8	NP_002171.2	P38935
IGHMBP2	XM_047426881.1 link	c.602T>C	p.Leu201Ser	missense_variant	5/15		XP_047282837.1
IGHMBP2	XM_017017671.3 link	c.602T>C	p.Leu201Ser	missense_variant	5/12		XP_016873160.1
IGHMBP2	XM_005273976.3 link	c.602T>C	p.Leu201Ser	missense_variant	5/9		XP_005274033.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGHMBP2	ENST00000255078.8 link	c.602T>C	p.Leu201Ser	missense_variant	5/15	1	NM_002180.3	ENSP00000255078.4		P38935

Frequencies

GnomAD3 genomes

AF:

0.763

AC:

116004

AN:

151978

Hom.:

45161

Cov.:

show subpopulations

Gnomad AFR

AF:

0.640

Gnomad AMI

AF:

0.910

Gnomad AMR

AF:

0.828

Gnomad ASJ

AF:

0.796

Gnomad EAS

AF:

0.488

Gnomad SAS

AF:

0.729

Gnomad FIN

AF:

0.759

Gnomad MID

AF:

0.797

Gnomad NFE

AF:

0.843

Gnomad OTH

AF:

0.793

GnomAD3 exomes

AF:

0.773

AC:

194369

AN:

251366

Hom.:

76473

AF XY:

0.777

AC XY:

105609

AN XY:

135852

show subpopulations

Gnomad AFR exome

AF:

0.637

Gnomad AMR exome

AF:

0.799

Gnomad ASJ exome

AF:

0.798

Gnomad EAS exome

AF:

0.481

Gnomad SAS exome

AF:

0.742

Gnomad FIN exome

AF:

0.761

Gnomad NFE exome

AF:

0.839

Gnomad OTH exome

AF:

0.795

GnomAD4 exome

AF:

0.819

AC:

1196697

AN:

1461732

Hom.:

493365

Cov.:

AF XY:

0.817

AC XY:

594292

AN XY:

727172

show subpopulations

Gnomad4 AFR exome

AF:

0.637

Gnomad4 AMR exome

AF:

0.799

Gnomad4 ASJ exome

AF:

0.798

Gnomad4 EAS exome

AF:

0.531

Gnomad4 SAS exome

AF:

0.745

Gnomad4 FIN exome

AF:

0.758

Gnomad4 NFE exome

AF:

0.846

Gnomad4 OTH exome

AF:

0.788

GnomAD4 genome

AF:

0.763

AC:

116087

AN:

152096

Hom.:

45193

Cov.:

AF XY:

0.762

AC XY:

56642

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.641

Gnomad4 AMR

AF:

0.829

Gnomad4 ASJ

AF:

0.796

Gnomad4 EAS

AF:

0.488

Gnomad4 SAS

AF:

0.728

Gnomad4 FIN

AF:

0.759

Gnomad4 NFE

AF:

0.843

Gnomad4 OTH

AF:

0.790

Alfa

AF:

0.823

Hom.:

134416

Bravo

AF:

0.762

TwinsUK

AF:

0.842

AC:

3122

ALSPAC

AF:

0.855

AC:

3297

ESP6500AA

AF:

0.650

AC:

2862

ESP6500EA

AF:

0.844

AC:

7250

ExAC

AF:

0.771

AC:

93660

Asia WGS

AF:

0.622

AC:

2165

AN:

3478

EpiCase

AF:

0.844

EpiControl

AF:

0.848

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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: 77% of total chromosomes in ExAC -
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	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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	-	- -

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

Labcorp Genetics (formerly Invitae), Labcorp

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

0.057

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.58

CADD

Benign

1.7

DANN

Benign

0.31

DEOGEN2

Benign

0.14

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.077

MetaRNN

Benign

7.0e-7

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.20

PrimateAI

Benign

0.36

PROVEAN

Benign

1.9

REVEL

Benign

0.14

Sift

Benign

0.26

Sift4G

Benign

0.78

Polyphen

0.0

Vest4

0.10

MPC

0.26

ClinPred

0.012

GERP RS

-1.6

Varity_R

0.24

gMVP

0.30

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