11-68939671-T-G

Position:

chr11-68939671-T-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_ModerateBS1BS2

The NM_002180.3(IGHMBP2):c.2922T>G(p.Asp974Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00189 in 1,612,916 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 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 0.0014 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0019 ( 4 hom. )

Consequence

IGHMBP2
NM_002180.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:4

Conservation

PhyloP100: -0.384

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 -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15927237).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0014 (213/152152) while in subpopulation NFE AF= 0.00234 (159/67984). AF 95% confidence interval is 0.00204. There are 1 homozygotes in gnomad4. There are 96 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGHMBP2	NM_002180.3 linkuse as main transcript	c.2922T>G	p.Asp974Glu	missense_variant	15/15	ENST00000255078.8	NP_002171.2	P38935
IGHMBP2	XM_017017670.3 linkuse as main transcript	c.1911T>G	p.Asp637Glu	missense_variant	11/11		XP_016873159.1
IGHMBP2	XM_005273975.4 linkuse as main transcript	c.1794T>G	p.Asp598Glu	missense_variant	8/8		XP_005274032.1
IGHMBP2	XM_011544994.2 linkuse as main transcript	c.1689T>G	p.Asp563Glu	missense_variant	8/8		XP_011543296.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGHMBP2	ENST00000255078.8 linkuse as main transcript	c.2922T>G	p.Asp974Glu	missense_variant	15/15	1	NM_002180.3	ENSP00000255078.4		P38935

Frequencies

GnomAD3 genomes

AF:

0.00140

AC:

213

AN:

152034

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000749

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000378

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00234

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00104

AC:

257

AN:

247262

Hom.:

AF XY:

0.00106

AC XY:

142

AN XY:

134116

show subpopulations

Gnomad AFR exome

AF:

0.000700

Gnomad AMR exome

AF:

0.000758

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.0000945

Gnomad NFE exome

AF:

0.00184

Gnomad OTH exome

AF:

0.00201

GnomAD4 exome

AF:

0.00195

AC:

2842

AN:

1460764

Hom.:

Cov.:

AF XY:

0.00185

AC XY:

1346

AN XY:

726662

show subpopulations

Gnomad4 AFR exome

AF:

0.000388

Gnomad4 AMR exome

AF:

0.000919

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.000378

Gnomad4 NFE exome

AF:

0.00237

Gnomad4 OTH exome

AF:

0.00209

GnomAD4 genome

AF:

0.00140

AC:

213

AN:

152152

Hom.:

Cov.:

AF XY:

0.00129

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.000746

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000378

Gnomad4 NFE

AF:

0.00234

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00190

Hom.:

Bravo

AF:

0.00148

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000682

AC:

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.000964

AC:

117

EpiCase

AF:

0.00207

EpiControl

AF:

0.00155

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 01, 2014	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The IGHMBP2 p.Asp974Glu variant was identified 1 of 58 proband chromosomes (frequency: 0.017) from an infant with distal spinal muscular atrophy with respiratory distress type 1 (SMARD1) who carried another variant of uncertain significance in the IGHMBP2 gene (Grohmann_2003_PMID: 14681881). The variant was identified in dbSNP (ID: rs147674615) and ClinVar (classified as uncertain significance by Athena diagnostics, ARUP laboratories, EGL Diagnostics, and Illuminal, and as likely benign by Invitae). The variant was identified in control databases in 304 of 278604 chromosomes (1 homozygous) at a frequency of 0.001091 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 239 of 126884 chromosomes (freq: 0.001884), Other in 12 of 7070 chromosomes (freq: 0.001697), African in 21 of 24426 chromosomes (freq: 0.00086), Latino in 28 of 35132 chromosomes (freq: 0.000797), European (Finnish) in 3 of 24636 chromosomes (freq: 0.000122) and South Asian in 1 of 30452 chromosomes (freq: 0.000033), but was not observed in the Ashkenazi Jewish or East Asian populations. The p.Asp974 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 15, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 13, 2023	The IGHMBP2 c.2922T>G; p.Asp974Glu variant (rs147674615) is reported in the literature in individuals with respiratory distress and/or sudden death (Grohmann 2003, Salfati 2019, Torkamani 2016), and in large cohorts of individuals with Charcot-Marie-Tooth disease or peripheral neuropathy (Antoniadi 2015, Volodarsky 2021). This variant is also reported in ClinVar (Variation ID: 194494), and is found in the general population with an overall allele frequency of 0.11% (304/278604 alleles, including a single homozygote) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.664). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Antoniadi T et al. Application of targeted multi-gene panel testing for the diagnosis of inherited peripheral neuropathy provides a high diagnostic yield with unexpected phenotype-genotype variability. BMC Med Genet. 2015 Sep 21;16:84. PMID: 26392352. Grohmann et al. Infantile spinal muscular atrophy with respiratory distress type 1 (SMARD1). Ann Neurol. 2003 Dec;54(6):719-24. PMID: 14681881. Salfati EL et al. Re-analysis of whole-exome sequencing data uncovers novel diagnostic variants and improves molecular diagnostic yields for sudden death and idiopathic diseases. Genome Med. 2019 Dec 17;11(1):83. PMID: 31847883. Torkamani A et al. Molecular Autopsy for Sudden Unexpected Death. JAMA. 2016 Oct 11;316(14):1492-1494. PMID: 27727376. Volodarsky M et al. Comprehensive genetic sequence and copy number analysis for Charcot-Marie-Tooth disease in a Canadian cohort of 2517 patients. J Med Genet. 2021 Apr;58(4):284-288. PMID: 32376792. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	IGHMBP2: BS1 -

Charcot-Marie-Tooth disease

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 27, 2023

The c.2922T>G (p.D974E) alteration is located in exon 15 (coding exon 15) of the IGHMBP2 gene. This alteration results from a T to G substitution at nucleotide position 2922, causing the aspartic acid (D) at amino acid position 974 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, 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

Apr 27, 2017

The IGHMBP2 c.2922T>G (p.Asp974Glu) missense variant has been reported in one study in which it is found in a compound heterozygous state in one individual with spinal muscular atrophy (Grohmann et al. 2003). Control data are unavailable for this variant, which it is reported at a frequency of 0.00163 in the European American population of the Exome Sequencing Project. The evidence for this variant is limited. The p.Asp974Glu variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for spinal muscular atrophy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Charcot-Marie-Tooth disease axonal type 2S

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 11, 2018

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

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 02, 2020

- -

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 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.030

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

Eigen

Benign

0.00052

Eigen_PC

Benign

-0.16

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.79

M_CAP

Benign

0.084

MetaRNN

Benign

0.16

MetaSVM

Uncertain

0.38

MutationAssessor

Uncertain

2.4

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.7

REVEL

Pathogenic

0.66

Sift

Benign

0.034

Sift4G

Benign

0.29

Polyphen

1.0

Vest4

0.72

MVP

0.90

MPC

0.24

ClinPred

0.047

GERP RS

-1.0

Varity_R

0.17

gMVP

0.30

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