rs17612126

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002180.3(IGHMBP2):c.2636C>A(p.Thr879Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.272 in 1,613,734 control chromosomes in the GnomAD database, including 63,713 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 4935 hom., cov: 32)

Exomes 𝑓: 0.28 ( 58778 hom. )

Consequence

IGHMBP2
NM_002180.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:13

Conservation

PhyloP100: -0.292

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=3.3271313E-4).

BP6

Variant 11-68938206-C-A is Benign according to our data. Variant chr11-68938206-C-A is described in ClinVar as [Benign]. Clinvar id is 194368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68938206-C-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.39 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGHMBP2	NM_002180.3 linkuse as main transcript	c.2636C>A	p.Thr879Lys	missense_variant	14/15	ENST00000255078.8	NP_002171.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGHMBP2	ENST00000255078.8 linkuse as main transcript	c.2636C>A	p.Thr879Lys	missense_variant	14/15	1	NM_002180.3	ENSP00000255078	P1

Frequencies

GnomAD3 genomes

AF:

0.225

AC:

34238

AN:

152000

Hom.:

4928

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0649

Gnomad AMI

AF:

0.449

Gnomad AMR

AF:

0.397

Gnomad ASJ

AF:

0.125

Gnomad EAS

AF:

0.245

Gnomad SAS

AF:

0.177

Gnomad FIN

AF:

0.265

Gnomad MID

AF:

0.206

Gnomad NFE

AF:

0.282

Gnomad OTH

AF:

0.219

GnomAD3 exomes

AF:

0.264

AC:

66271

AN:

251418

Hom.:

10210

AF XY:

0.256

AC XY:

34839

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.0622

Gnomad AMR exome

AF:

0.464

Gnomad ASJ exome

AF:

0.135

Gnomad EAS exome

AF:

0.245

Gnomad SAS exome

AF:

0.180

Gnomad FIN exome

AF:

0.247

Gnomad NFE exome

AF:

0.272

Gnomad OTH exome

AF:

0.257

GnomAD4 exome

AF:

0.277

AC:

404789

AN:

1461616

Hom.:

58778

Cov.:

AF XY:

0.273

AC XY:

198447

AN XY:

727156

show subpopulations

Gnomad4 AFR exome

AF:

0.0517

Gnomad4 AMR exome

AF:

0.457

Gnomad4 ASJ exome

AF:

0.138

Gnomad4 EAS exome

AF:

0.255

Gnomad4 SAS exome

AF:

0.183

Gnomad4 FIN exome

AF:

0.246

Gnomad4 NFE exome

AF:

0.291

Gnomad4 OTH exome

AF:

0.247

GnomAD4 genome

AF:

0.225

AC:

34253

AN:

152118

Hom.:

4935

Cov.:

AF XY:

0.228

AC XY:

16948

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.0648

Gnomad4 AMR

AF:

0.398

Gnomad4 ASJ

AF:

0.125

Gnomad4 EAS

AF:

0.245

Gnomad4 SAS

AF:

0.177

Gnomad4 FIN

AF:

0.265

Gnomad4 NFE

AF:

0.282

Gnomad4 OTH

AF:

0.218

Alfa

AF:

0.260

Hom.:

9358

Bravo

AF:

0.231

TwinsUK

AF:

0.297

AC:

1100

ALSPAC

AF:

0.303

AC:

1169

ESP6500AA

AF:

0.0777

AC:

342

ESP6500EA

AF:

0.278

AC:

2387

ExAC

AF:

0.250

AC:

30305

Asia WGS

AF:

0.197

AC:

684

AN:

3478

EpiCase

AF:

0.280

EpiControl

AF:

0.270

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 13, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 25% of total chromosomes in ExAC -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 24022109, 11528396, 20981092, 20220177, 16458836, 21228398, 15797190) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Autosomal recessive distal spinal muscular atrophy 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 30, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Neuronopathy, distal hereditary motor, autosomal dominant

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

- -

Charcot-Marie-Tooth disease

Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Charcot-Marie-Tooth disease axonal type 2S

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.49

CADD

Benign

0.24

DANN

Benign

0.81

DEOGEN2

Benign

0.060

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.47

MetaRNN

Benign

0.00033

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.2

MutationTaster

Benign

1.0

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.24

REVEL

Benign

0.21

Sift

Benign

0.90

Sift4G

Benign

1.0

Polyphen

0.21

Vest4

0.050

MPC

0.23

ClinPred

0.0042

GERP RS

-3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.062

gMVP

0.20

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