chr11-68929315-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_002180.3(IGHMBP2):c.1193C>T(p.Ala398Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00259 in 1,613,602 control chromosomes in the GnomAD database, including 15 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 0.0018 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0027 ( 13 hom. )

Consequence

IGHMBP2
NM_002180.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:8

Conservation

PhyloP100: 7.58

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 -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12899712).

BP6

Variant 11-68929315-C-T is Benign according to our data. Variant chr11-68929315-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 234315.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Benign=1, Uncertain_significance=1}. Variant chr11-68929315-C-T is described in Lovd as [Likely_pathogenic].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00183 (278/152270) while in subpopulation NFE AF= 0.00288 (196/68008). AF 95% confidence interval is 0.00255. There are 2 homozygotes in gnomad4. There are 134 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGHMBP2	NM_002180.3 link	c.1193C>T	p.Ala398Val	missense_variant	Exon 8 of 15	ENST00000255078.8	NP_002171.2	P38935

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGHMBP2	ENST00000255078.8 link	c.1193C>T	p.Ala398Val	missense_variant	Exon 8 of 15	1	NM_002180.3	ENSP00000255078.4		P38935

Frequencies

GnomAD3 genomes

AF:

0.00183

AC:

278

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.00367

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00288

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.00245

AC:

615

AN:

250856

Hom.:

AF XY:

0.00248

AC XY:

337

AN XY:

135662

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00328

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00219

Gnomad FIN exome

AF:

0.00357

Gnomad NFE exome

AF:

0.00370

Gnomad OTH exome

AF:

0.00180

GnomAD4 exome

AF:

0.00267

AC:

3901

AN:

1461332

Hom.:

Cov.:

AF XY:

0.00257

AC XY:

1871

AN XY:

727000

show subpopulations

Gnomad4 AFR exome

AF:

0.000388

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00264

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00227

Gnomad4 FIN exome

AF:

0.00437

Gnomad4 NFE exome

AF:

0.00294

Gnomad4 OTH exome

AF:

0.00179

GnomAD4 genome

AF:

0.00183

AC:

278

AN:

152270

Hom.:

Cov.:

AF XY:

0.00180

AC XY:

134

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.000577

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00186

Gnomad4 FIN

AF:

0.00367

Gnomad4 NFE

AF:

0.00288

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.00246

Hom.:

Bravo

AF:

0.00149

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.00221

AC:

ExAC

AF:

0.00290

AC:

352

EpiCase

AF:

0.00207

EpiControl

AF:

0.00267

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:3

Oct 13, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 23, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26467025, 26392352) -

Sep 22, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

IGHMBP2: PM5, BS2 -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease

Benign:1

Molecular Genetics Laboratory, London Health Sciences Centre

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

IGHMBP2-related disorder

Benign:1

Jan 31, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely 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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Benign:1

Sep 23, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Autosomal recessive distal spinal muscular atrophy 1

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.090

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.62

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.83

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.13

MetaSVM

Uncertain

-0.12

MutationAssessor

Benign

0.70

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.8

REVEL

Uncertain

0.58

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.92

MVP

0.79

MPC

0.75

ClinPred

0.070

GERP RS

4.0

Varity_R

0.92

gMVP

0.79

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