rs118015540

Positions:

chr11-68906247-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002180.3(IGHMBP2):c.256+9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00773 in 1,613,624 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0057 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0079 ( 59 hom. )

Consequence

IGHMBP2
NM_002180.3 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.797

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 (BayesDel_noAF=-0.88).

BP6

Variant 11-68906247-G-A is Benign according to our data. Variant chr11-68906247-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 137568.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68906247-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00567 (863/152306) while in subpopulation NFE AF= 0.00938 (638/68026). AF 95% confidence interval is 0.00878. There are 4 homozygotes in gnomad4. There are 386 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE
IGHMBP2	NM_002180.3 linkuse as main transcript	c.256+9G>A	intron_variant	ENST00000255078.8
IGHMBP2	XM_005273976.3 linkuse as main transcript	c.256+9G>A	intron_variant
IGHMBP2	XM_017017671.3 linkuse as main transcript	c.256+9G>A	intron_variant
IGHMBP2	XM_047426881.1 linkuse as main transcript	c.256+9G>A	intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGHMBP2	ENST00000255078.8 linkuse as main transcript	c.256+9G>A		intron_variant		1	NM_002180.3	P1

Frequencies

GnomAD3 genomes

AF:

0.00567

AC:

863

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00176

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00543

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00500

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00938

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00508

AC:

1277

AN:

251290

Hom.:

AF XY:

0.00511

AC XY:

694

AN XY:

135828

show subpopulations

Gnomad AFR exome

AF:

0.00234

Gnomad AMR exome

AF:

0.00298

Gnomad ASJ exome

AF:

0.000893

Gnomad EAS exome

AF:

0.000326

Gnomad SAS exome

AF:

0.000817

Gnomad FIN exome

AF:

0.00476

Gnomad NFE exome

AF:

0.00836

Gnomad OTH exome

AF:

0.00701

GnomAD4 exome

AF:

0.00795

AC:

11612

AN:

1461318

Hom.:

Cov.:

AF XY:

0.00777

AC XY:

5648

AN XY:

727022

show subpopulations

Gnomad4 AFR exome

AF:

0.00126

Gnomad4 AMR exome

AF:

0.00333

Gnomad4 ASJ exome

AF:

0.00142

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.000846

Gnomad4 FIN exome

AF:

0.00511

Gnomad4 NFE exome

AF:

0.00960

Gnomad4 OTH exome

AF:

0.00573

GnomAD4 genome

AF:

0.00567

AC:

863

AN:

152306

Hom.:

Cov.:

AF XY:

0.00518

AC XY:

386

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00176

Gnomad4 AMR

AF:

0.00543

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00500

Gnomad4 NFE

AF:

0.00938

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00694

Hom.:

Bravo

AF:

0.00574

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 12, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 07, 2016	- -

Autosomal recessive distal spinal muscular atrophy 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	IGHMBP2: BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 01, 2023	- -

Charcot-Marie-Tooth disease

Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

IGHMBP2-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 19, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

1.2

DANN

Benign

0.94

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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