rs117061430

Positions:

Variant summary

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

The ENST00000255078.8(IGHMBP2):c.151C>G(p.Gln51Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00594 in 1,614,180 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0049 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0061 ( 41 hom. )

Consequence

IGHMBP2
ENST00000255078.8 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.85

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=0.0074187815).

BP6

Variant 11-68906133-C-G is Benign according to our data. Variant chr11-68906133-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 258557.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68906133-C-G is described in Lovd as [Benign]. Variant chr11-68906133-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00487 (741/152306) while in subpopulation NFE AF= 0.00691 (470/68022). AF 95% confidence interval is 0.00639. There are 6 homozygotes in gnomad4. There are 389 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
IGHMBP2	NM_002180.3 linkuse as main transcript	c.151C>G	p.Gln51Glu	missense_variant	2/15	ENST00000255078.8	NP_002171.2
IGHMBP2	XM_047426881.1 linkuse as main transcript	c.151C>G	p.Gln51Glu	missense_variant	2/15		XP_047282837.1
IGHMBP2	XM_017017671.3 linkuse as main transcript	c.151C>G	p.Gln51Glu	missense_variant	2/12		XP_016873160.1
IGHMBP2	XM_005273976.3 linkuse as main transcript	c.151C>G	p.Gln51Glu	missense_variant	2/9		XP_005274033.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGHMBP2	ENST00000255078.8 linkuse as main transcript	c.151C>G	p.Gln51Glu	missense_variant	2/15	1	NM_002180.3	ENSP00000255078	P1

Frequencies

GnomAD3 genomes

AF:

0.00488

AC:

742

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00123

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00170

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00310

Gnomad FIN

AF:

0.0161

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00691

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00606

AC:

1525

AN:

251490

Hom.:

AF XY:

0.00604

AC XY:

821

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.00127

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00242

Gnomad FIN exome

AF:

0.0184

Gnomad NFE exome

AF:

0.00839

Gnomad OTH exome

AF:

0.00505

GnomAD4 exome

AF:

0.00606

AC:

8853

AN:

1461874

Hom.:

Cov.:

AF XY:

0.00592

AC XY:

4305

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00114

Gnomad4 AMR exome

AF:

0.00148

Gnomad4 ASJ exome

AF:

0.000268

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00248

Gnomad4 FIN exome

AF:

0.0183

Gnomad4 NFE exome

AF:

0.00655

Gnomad4 OTH exome

AF:

0.00439

GnomAD4 genome

AF:

0.00487

AC:

741

AN:

152306

Hom.:

Cov.:

AF XY:

0.00522

AC XY:

389

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00123

Gnomad4 AMR

AF:

0.00163

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00311

Gnomad4 FIN

AF:

0.0161

Gnomad4 NFE

AF:

0.00691

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00562

Hom.:

Bravo

AF:

0.00378

TwinsUK

AF:

0.00755

AC:

ALSPAC

AF:

0.00675

AC:

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.00687

AC:

ExAC

AF:

0.00628

AC:

762

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00583

EpiControl

AF:

0.00557

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, criteria provided, single submitter	clinical testing	GeneDx	Apr 04, 2016	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)	Dec 22, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Autosomal recessive distal spinal muscular atrophy 1

Benign:2

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. -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Mar 11, 2016	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	IGHMBP2: BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2023	- -

Charcot-Marie-Tooth disease

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

IGHMBP2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 27, 2023

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.17

CADD

Benign

DANN

Benign

0.83

DEOGEN2

Benign

0.086

T;.

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.20

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.85

T;T

MetaRNN

Benign

0.0074

T;T

MetaSVM

Benign

-0.45

MutationAssessor

Benign

1.3

L;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.67

N;N

REVEL

Benign

0.20

Sift

Benign

0.97

T;T

Sift4G

Benign

0.92

T;T

Polyphen

0.0040

B;.

Vest4

0.45

MVP

0.83

MPC

0.21

ClinPred

0.015

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.30

gMVP

0.51

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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