11-68906147-G-C

Position:

chr11-68906147-G-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6

The NM_002180.3(IGHMBP2):c.165G>C(p.Gln55His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000392 in 1,614,068 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 0.00042 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00039 ( 1 hom. )

Consequence

IGHMBP2
NM_002180.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:3

Conservation

PhyloP100: 2.88

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 -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12896848).

BP6

Variant 11-68906147-G-C is Benign according to our data. Variant chr11-68906147-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 426960.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=5}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGHMBP2	NM_002180.3 linkuse as main transcript	c.165G>C	p.Gln55His	missense_variant	2/15	ENST00000255078.8	NP_002171.2	P38935
IGHMBP2	XM_047426881.1 linkuse as main transcript	c.165G>C	p.Gln55His	missense_variant	2/15		XP_047282837.1
IGHMBP2	XM_017017671.3 linkuse as main transcript	c.165G>C	p.Gln55His	missense_variant	2/12		XP_016873160.1
IGHMBP2	XM_005273976.3 linkuse as main transcript	c.165G>C	p.Gln55His	missense_variant	2/9		XP_005274033.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGHMBP2	ENST00000255078.8 linkuse as main transcript	c.165G>C	p.Gln55His	missense_variant	2/15	1	NM_002180.3	ENSP00000255078.4		P38935

Frequencies

GnomAD3 genomes

AF:

0.000420

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00236

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000485

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000585

AC:

147

AN:

251490

Hom.:

AF XY:

0.000618

AC XY:

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.00236

Gnomad NFE exome

AF:

0.000703

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.000389

AC:

568

AN:

1461868

Hom.:

Cov.:

AF XY:

0.000424

AC XY:

308

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.00255

Gnomad4 NFE exome

AF:

0.000362

Gnomad4 OTH exome

AF:

0.000248

GnomAD4 genome

AF:

0.000420

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.000538

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00236

Gnomad4 NFE

AF:

0.000485

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000445

Hom.:

Bravo

AF:

0.000178

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000582

AC:

ExAC

AF:

0.000560

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 10, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 22, 2021	This variant is associated with the following publications: (PMID: 25025039, 32376792) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 18, 2020	- -

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

May 10, 2022

The p.Q55H variant (also known as c.165G>C), located in coding exon 2 of the IGHMBP2 gene, results from a G to C substitution at nucleotide position 165. The glutamine at codon 55 is replaced by histidine, an amino acid with highly similar properties. 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. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 08, 2022

Variant summary: IGHMBP2 c.165G>C (p.Gln55His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00058 in 251490 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in IGHMBP2 causing Charcot-Marie-Tooth Disease, Axonal, Type 2S, allowing no conclusion about variant significance. Although reported as a VUS in settings of multigene panel testing among cohorts of individuals with suspected Charcot-Marie-Tooth (CMT) disease (example, Volodarsky_2021), to our knowledge, no penetrant association of c.165G>C in individuals affected with Charcot-Marie-Tooth Disease, Axonal, Type 2S and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as likely benign. -

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 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

T;.

Eigen

Benign

0.11

Eigen_PC

Benign

0.024

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.83

T;T

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.13

T;T

MetaSVM

Uncertain

0.29

MutationAssessor

Pathogenic

2.9

M;.

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-2.2

N;D

REVEL

Uncertain

0.55

Sift

Benign

0.19

T;T

Sift4G

Benign

0.54

T;D

Polyphen

0.99

D;.

Vest4

0.63

MutPred

0.40

Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);

MVP

0.92

MPC

0.67

ClinPred

0.15

GERP RS

2.7

Varity_R

0.20

gMVP

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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