rs724159994

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_002180.3(IGHMBP2):c.2911_2912del(p.Arg971GlufsTer4) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000144 in 1,613,246 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

IGHMBP2
NM_002180.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11U:2

Conservation

PhyloP100: 8.59

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 Pathogenic. Variant got 12 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0245 CDS is truncated, and there are 2 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-68939657-CAG-C is Pathogenic according to our data. Variant chr11-68939657-CAG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 162195.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68939657-CAG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
IGHMBP2	NM_002180.3 linkuse as main transcript	c.2911_2912del	p.Arg971GlufsTer4	frameshift_variant	15/15	ENST00000255078.8
IGHMBP2	XM_005273975.4 linkuse as main transcript	c.1783_1784del	p.Arg595GlufsTer4	frameshift_variant	8/8
IGHMBP2	XM_011544994.2 linkuse as main transcript	c.1678_1679del	p.Arg560GlufsTer4	frameshift_variant	8/8
IGHMBP2	XM_017017670.3 linkuse as main transcript	c.1900_1901del	p.Arg634GlufsTer4	frameshift_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGHMBP2	ENST00000255078.8 linkuse as main transcript	c.2911_2912del	p.Arg971GlufsTer4	frameshift_variant	15/15	1	NM_002180.3	P1

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000353

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000121

AC:

AN:

248290

Hom.:

AF XY:

0.000126

AC XY:

AN XY:

134614

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000582

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000250

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000141

AC:

206

AN:

1461044

Hom.:

AF XY:

0.000131

AC XY:

AN XY:

726828

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000448

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000174

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.000171

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000353

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.000110

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 22, 2022	PP1, PM2, PM3_strong, PVS1_moderate -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 18, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 16, 2022	Frameshift variant predicted to result in protein truncation as the last 23 amino acids are lost and replaced with 3 incorrect amino acids; This variant is associated with the following publications: (PMID: 26298607, 30373780, 31827005, 33084218, 32376792, 26392352) -

Charcot-Marie-Tooth disease axonal type 2S

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 13, 2023	Variant summary: IGHMBP2 c.2911_2912delAG (p.Arg971GlufsX4) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein. The variant allele was found at a frequency of 0.00012 in 248290 control chromosomes (gnomAD). c.2911_2912delAG has been reported in the literature in individuals affected with Charcot-Marie Tooth disease type 2 (examples: Bacquet_2018, Cottenie_2014). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 30373780, 31827005). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variants as pathogenic (n=4) and VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 03, 2015	- -

Charcot-Marie-Tooth disease

Pathogenic:1Uncertain:1

Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, London Health Sciences Centre	-	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 14, 2021

The c.2911_2912delAG (p.R971Efs*4) alteration, located in exon 15 (coding exon 15) of the IGHMBP2 gene, consists of a deletion of 2 nucleotides from position 2911 to 2912, causing a translational frameshift with a predicted alternate stop codon after 4 amino acids. This alteration occurs at the 3' terminus of the IGHMBP2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 23 amino acids of the protein. However, premature stop codons are typically deleterious in nature. Based on data from gnomAD, this allele has an overall frequency of 0.012% (33/279672) total alleles studied. The highest observed frequency was 0.024% (31/127458) of European (non-Finnish) alleles. This variant has been reported in conjunction with other pathogenic mutations in IGHMBP2 in multiple unrelated patients with IGHMBP2-related neuropathy (Cottenie, 2014; Bacquet, 2018; Cortese, 2020; Schottmann, 2015). This alteration has also been detected in the homozygous state in a patient reported to have Charcot-Marie-Tooth disease; however, clinical information was limited (Antoniadi, 2015). Based on the available evidence, this alteration is classified as pathogenic. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 23, 2024

This sequence change creates a premature translational stop signal (p.Arg971Glufs*4) in the IGHMBP2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 23 amino acid(s) of the IGHMBP2 protein. This variant is present in population databases (rs572973851, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with peripheral neuropathy (PMID: 15269181, 25439726, 25568292, 26392352; Invitae). ClinVar contains an entry for this variant (Variation ID: 162195). For these reasons, this variant has been classified as Pathogenic. -

Autosomal recessive distal spinal muscular atrophy 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Consultorio y Laboratorio de Neurogenética, Hospital JM Ramos Mejia

- -

Distal spinal muscular atrophy

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Institute of Human Genetics, Cologne University

Apr 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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