rs1249463

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_002180.3(IGHMBP2):c.57T>C(p.Leu19=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.814 in 1,550,292 control chromosomes in the GnomAD database, including 517,889 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.76 ( 44837 hom., cov: 34)

Exomes 𝑓: 0.82 ( 473052 hom. )

Consequence

IGHMBP2
NM_002180.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 0.0150

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 11-68904009-T-C is Benign according to our data. Variant chr11-68904009-T-C is described in ClinVar as [Benign]. Clinvar id is 258575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68904009-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.015 with no splicing effect.

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
IGHMBP2	NM_002180.3 linkuse as main transcript	c.57T>C	p.Leu19=	synonymous_variant	1/15	ENST00000255078.8	NP_002171.2
IGHMBP2	XM_047426881.1 linkuse as main transcript	c.57T>C	p.Leu19=	synonymous_variant	1/15		XP_047282837.1
IGHMBP2	XM_017017671.3 linkuse as main transcript	c.57T>C	p.Leu19=	synonymous_variant	1/12		XP_016873160.1
IGHMBP2	XM_005273976.3 linkuse as main transcript	c.57T>C	p.Leu19=	synonymous_variant	1/9		XP_005274033.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGHMBP2	ENST00000255078.8 linkuse as main transcript	c.57T>C	p.Leu19=	synonymous_variant	1/15	1	NM_002180.3	ENSP00000255078	P1

Frequencies

GnomAD3 genomes

AF:

0.759

AC:

115447

AN:

152028

Hom.:

44809

Cov.:

show subpopulations

Gnomad AFR

AF:

0.627

Gnomad AMI

AF:

0.910

Gnomad AMR

AF:

0.826

Gnomad ASJ

AF:

0.796

Gnomad EAS

AF:

0.489

Gnomad SAS

AF:

0.731

Gnomad FIN

AF:

0.758

Gnomad MID

AF:

0.803

Gnomad NFE

AF:

0.843

Gnomad OTH

AF:

0.788

GnomAD3 exomes

AF:

0.769

AC:

118247

AN:

153684

Hom.:

46316

AF XY:

0.772

AC XY:

62926

AN XY:

81544

show subpopulations

Gnomad AFR exome

AF:

0.618

Gnomad AMR exome

AF:

0.799

Gnomad ASJ exome

AF:

0.797

Gnomad EAS exome

AF:

0.472

Gnomad SAS exome

AF:

0.743

Gnomad FIN exome

AF:

0.757

Gnomad NFE exome

AF:

0.844

Gnomad OTH exome

AF:

0.795

GnomAD4 exome

AF:

0.820

AC:

1146146

AN:

1398142

Hom.:

473052

Cov.:

AF XY:

0.818

AC XY:

564363

AN XY:

689706

show subpopulations

Gnomad4 AFR exome

AF:

0.625

Gnomad4 AMR exome

AF:

0.798

Gnomad4 ASJ exome

AF:

0.798

Gnomad4 EAS exome

AF:

0.533

Gnomad4 SAS exome

AF:

0.746

Gnomad4 FIN exome

AF:

0.757

Gnomad4 NFE exome

AF:

0.846

Gnomad4 OTH exome

AF:

0.788

GnomAD4 genome

AF:

0.759

AC:

115526

AN:

152150

Hom.:

44837

Cov.:

AF XY:

0.758

AC XY:

56397

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.628

Gnomad4 AMR

AF:

0.826

Gnomad4 ASJ

AF:

0.796

Gnomad4 EAS

AF:

0.488

Gnomad4 SAS

AF:

0.730

Gnomad4 FIN

AF:

0.758

Gnomad4 NFE

AF:

0.843

Gnomad4 OTH

AF:

0.786

Alfa

AF:

0.818

Hom.:

30016

Bravo

AF:

0.758

Asia WGS

AF:

0.622

AC:

2162

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 29, 2016	- -
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	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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: 76% of total chromosomes in ExAC -

not provided

Benign:3

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

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

BayesDel_noAF

Benign

-0.78

CADD

Benign

DANN

Benign

0.79

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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