rs756985703

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM1PP5BP4

The NM_002180.3(IGHMBP2):c.1591C>A(p.Pro531Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,612,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

IGHMBP2
NM_002180.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:4

Conservation

PhyloP100: 2.74

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive distal spinal muscular atrophy 1
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
Charcot-Marie-Tooth disease axonal type 2S
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
hereditary peripheral neuropathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

IGHMBP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_002180.3

PP5

Variant 11-68934517-C-A is Pathogenic according to our data. Variant chr11-68934517-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 204302.

BP4

Computational evidence support a benign effect (MetaRNN=0.36226737). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGHMBP2	NM_002180.3 link	c.1591C>A	p.Pro531Thr	missense_variant	Exon 11 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.1591C>A	p.Pro531Thr	missense_variant	Exon 11 of 15	1	NM_002180.3	ENSP00000255078.4		P38935

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000363

AC:

AN:

247920

AF XY:

0.0000522

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1460644

Hom.:

Cov.:

AF XY:

0.0000317

AC XY:

AN XY:

726460

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33448

American (AMR)

AF:

0.00

AC:

AN:

44600

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39664

South Asian (SAS)

AF:

0.000314

AC:

AN:

85906

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53370

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111422

Other (OTH)

AF:

0.00

AC:

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41458

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000741

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease axonal type 2S

Pathogenic:1Uncertain:2

Jun 28, 2023

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

A heterozygous missense substitution (p.Pro531Thr) lies in exon 11 of the IGHMBP2 gene and alters a mildly conserved residue in the protein. The variant c.1591C>A has a minor allele frequency of 0.004% in the gnomAD database. The variant is predicted to be damaging by FATHM. In summary, the variant meets our criteria to be classified as variant of uncertain significance. -

Feb 01, 2024

Neuberg Centre For Genomic Medicine, NCGM

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has been reported previously in homozygous or compound heterozygous state in individuals affected with CharcotMarie Tooth Disease Type 2 (Cottenie et al., 2014), This variant in IGHMBP2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. -

Jul 12, 2023

3billion

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.68; 3Cnet: 0.30). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000204302 /PMID: 25439726).The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 25439726). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Autosomal recessive distal spinal muscular atrophy 1

Pathogenic:1

Lifecell International Pvt. Ltd

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

A Heterozygous Missense variant c.1591C>A in Exon 11 of the IGHMBP2 gene that results in the amino acid substitution p.Pro531Thr was identified. The observed variant has a minor allele frequency of 0.00004% in gnomAD exomes and is novel in genomes. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Conflicting Interpretations Likely Pathogenic/Uncertain Significance [Variation ID: 204302]. The observed variation has been previously reported in patients affected with Neuropathy (Cottenie, Ellen et al., 2014). For these reasons, this variant has been classified as Likely Pathogenic. -

Charcot-Marie-Tooth disease

Uncertain:1

Inherited Neuropathy Consortium

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

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

Uncertain:1

Jun 15, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 531 of the IGHMBP2 protein (p.Pro531Thr). This variant is present in population databases (rs756985703, gnomAD 0.03%). This missense change has been observed in individual(s) with Charcot-Marie Tooth disease type 2 and/or Down syndrome (PMID: 25439726). ClinVar contains an entry for this variant (Variation ID: 204302). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt IGHMBP2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.70

DEOGEN2

Uncertain

0.45

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.11

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.36

MetaSVM

Benign

-0.83

MutationAssessor

Benign

0.26

PhyloP100

2.7

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.41

REVEL

Pathogenic

0.68

Sift

Benign

0.26

Sift4G

Benign

0.32

Polyphen

0.034

Vest4

0.70

MutPred

0.49

Gain of catalytic residue at P531 (P = 0.0466);

MVP

0.66

MPC

0.30

ClinPred

0.035

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.16

gMVP

0.35

Mutation Taster

=33/67

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over