chr11-68936506-G-A

Position:

chr11-68936506-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_002180.3(IGHMBP2):c.2026G>A(p.Gly676Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000154 in 1,613,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

IGHMBP2
NM_002180.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: -0.514

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:

IGHMBP2 (HGNC:):

IGHMBP2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.01816243).

BP6

Variant 11-68936506-G-A is Benign according to our data. Variant chr11-68936506-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 439819.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000387 (59/152316) while in subpopulation AFR AF= 0.00103 (43/41560). AF 95% confidence interval is 0.000789. There are 0 homozygotes in gnomad4. There are 27 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGHMBP2	NM_002180.3 linkuse as main transcript	c.2026G>A	p.Gly676Arg	missense_variant	13/15	ENST00000255078.8	NP_002171.2	P38935

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGHMBP2	ENST00000255078.8 linkuse as main transcript	c.2026G>A	p.Gly676Arg	missense_variant	13/15	1	NM_002180.3	ENSP00000255078.4		P38935

Frequencies

GnomAD3 genomes

AF:

0.000388

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00104

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000132

AC:

AN:

250168

Hom.:

AF XY:

0.000126

AC XY:

AN XY:

135422

show subpopulations

Gnomad AFR exome

AF:

0.000938

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000124

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000130

AC:

190

AN:

1461348

Hom.:

Cov.:

AF XY:

0.000118

AC XY:

AN XY:

726996

show subpopulations

Gnomad4 AFR exome

AF:

0.00114

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000121

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000387

AC:

AN:

152316

Hom.:

Cov.:

AF XY:

0.000362

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.00103

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000160

Hom.:

Bravo

AF:

0.000348

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.000173

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 08, 2016

- -

Autosomal recessive distal spinal muscular atrophy 1

Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 01, 2021

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function -

Autosomal recessive distal spinal muscular atrophy 1;C4015349:Charcot-Marie-Tooth disease axonal type 2S

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 21, 2024

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 26, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.37

CADD

Benign

3.7

DANN

Benign

0.88

DEOGEN2

Benign

0.069

Eigen

Benign

-0.99

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.060

LIST_S2

Benign

0.52

M_CAP

Benign

0.024

MetaRNN

Benign

0.018

MetaSVM

Benign

-0.57

MutationAssessor

Benign

1.2

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.39

REVEL

Benign

0.20

Sift

Benign

0.28

Sift4G

Benign

0.42

Polyphen

0.44

Vest4

0.097

MutPred

0.18

Gain of MoRF binding (P = 0.0241);

MVP

0.79

MPC

0.23

ClinPred

0.0046

GERP RS

-2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.090

gMVP

0.42

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