rs147674615

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

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. 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:6B:5O:1

Conservation

PhyloP100: -0.384

Publications

12 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: Ambry Genetics, Laboratory for Molecular Medicine, Orphanet, 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: Benign. The variant received -11 ACMG points.

BP4

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

BP6

Variant 11-68939671-T-G is Benign according to our data. Variant chr11-68939671-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 194494.

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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002180.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGHMBP2	NM_002180.3	MANE Select	c.2922T>G	p.Asp974Glu	missense	Exon 15 of 15	NP_002171.2	P38935

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IGHMBP2	ENST00000255078.8	TSL:1 MANE Select	c.2922T>G	p.Asp974Glu	missense	Exon 15 of 15	ENSP00000255078.4	P38935
IGHMBP2	ENST00000544521.1	TSL:1	n.753T>G		non_coding_transcript_exon	Exon 2 of 2
IGHMBP2	ENST00000925063.1		c.2739T>G	p.Asp913Glu	missense	Exon 14 of 14	ENSP00000595122.1

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

GnomAD2 exomes

AF:

0.00104

AC:

257

AN:

247262

AF XY:

0.00106

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 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

African (AFR)

AF:

0.000388

AC:

AN:

33470

American (AMR)

AF:

0.000919

AC:

AN:

44620

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26060

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.000139

AC:

AN:

86150

European-Finnish (FIN)

AF:

0.000378

AC:

AN:

52966

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5702

European-Non Finnish (NFE)

AF:

0.00237

AC:

2630

AN:

1111782

Other (OTH)

AF:

0.00209

AC:

126

AN:

60324

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

159

318

477

636

795

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

208

312

416

520

<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:

0.00140

AC:

213

AN:

152152

Hom.:

Cov.:

AF XY:

0.00129

AC XY:

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.000746

AC:

AN:

41530

American (AMR)

AF:

0.00118

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5150

South Asian (SAS)

AF:

0.00

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.000378

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00234

AC:

159

AN:

67984

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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:

0.00180

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

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

not specified (2)

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

Charcot-Marie-Tooth disease (1)

Charcot-Marie-Tooth disease axonal type 2S (1)

Inborn genetic diseases (1)

Autosomal recessive distal spinal muscular atrophy 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.030

CADD

Benign

(source)

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

PhyloP100

-0.38

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

Mutation Taster

=77/23

polymorphism

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over