chr11-68914878-C-G

Position:

chr11-68914878-C-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_002180.3(IGHMBP2):c.767C>G(p.Ala256Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000703 in 1,614,256 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00069 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00070 ( 0 hom. )

Consequence

IGHMBP2
NM_002180.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:1

Conservation

PhyloP100: 5.47

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 Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.018211573).

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000689 (105/152362) while in subpopulation SAS AF= 0.00145 (7/4832). AF 95% confidence interval is 0.000679. There are 1 homozygotes in gnomad4. There are 52 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGHMBP2	NM_002180.3 linkuse as main transcript	c.767C>G	p.Ala256Gly	missense_variant	6/15	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.767C>G	p.Ala256Gly	missense_variant	6/15	1	NM_002180.3	ENSP00000255078.4		P38935

Frequencies

GnomAD3 genomes

AF:

0.000690

AC:

105

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000723

Gnomad AMI

AF:

0.0263

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000852

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000891

AC:

224

AN:

251456

Hom.:

AF XY:

0.00113

AC XY:

154

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00110

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00173

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.00101

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.000705

AC:

1030

AN:

1461894

Hom.:

Cov.:

AF XY:

0.000771

AC XY:

561

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.00107

Gnomad4 ASJ exome

AF:

0.000268

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00153

Gnomad4 FIN exome

AF:

0.000131

Gnomad4 NFE exome

AF:

0.000671

Gnomad4 OTH exome

AF:

0.000927

GnomAD4 genome

AF:

0.000689

AC:

105

AN:

152362

Hom.:

Cov.:

AF XY:

0.000698

AC XY:

AN XY:

74514

show subpopulations

Gnomad4 AFR

AF:

0.0000721

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000853

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000960

Hom.:

Bravo

AF:

0.000812

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000932

AC:

ExAC

AF:

0.000947

AC:

115

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000927

EpiControl

AF:

0.00136

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 19, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 07, 2024	Observed in two unrelated patients with IGHMBP2-related disorders in published literature (PMID: 26257172, 28251916); Reported previously as a variant of uncertain significance in a patient with suspected Charcot-Marie-Tooth disease; however, it was unclear if a second variant was identified (PMID: 32376792); Published functional studies suggested that this variant is partially functional (PMID: 36077311); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28251916, 26257172, 25439726, 24388491, 22965130, 32376792, 36077311) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 28, 2023	- -

Charcot-Marie-Tooth disease

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Jul 01, 2015

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2022

The p.A256G variant (also known as c.767C>G), located in coding exon 6 of the IGHMBP2 gene, results from a C to G substitution at nucleotide position 767. The alanine at codon 256 is replaced by glycine, an amino acid with similar properties. This alteration was reported in a patient with congenital hypomyelinating neuropathy who also had two additional alterations in IGHMBP2 although parental samples were unavailable to determine phase (Gonzaga-Jauregui C et al. Cell Rep, 2015 Aug;12:1169-83). This alteration was also reported in the heterozygous state in a young boy with features of distal hereditary motor neuronopathy (Bansagi B et al. Neurology, 2017 Mar;88:1226-1234), and in an individual with a diagnosis of Charcot-Marie-Tooth disease type 2 with limited clinical detail (Antoniadi T et al. BMC Med Genet, 2015 Sep;16:84). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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. -

Charcot-Marie-Tooth disease axonal type 2S

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 26, 2018

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

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

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.55

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.84

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.018

MetaSVM

Uncertain

-0.026

MutationAssessor

Benign

1.7

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-3.1

REVEL

Uncertain

0.53

Sift

Uncertain

0.010

Sift4G

Uncertain

0.0050

Polyphen

0.89

Vest4

0.53

MVP

0.86

MPC

0.72

ClinPred

0.13

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.87

gMVP

0.39

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