rs2275996

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002180.3(IGHMBP2):c.2782G>A(p.Glu928Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00577 in 1,607,640 control chromosomes in the GnomAD database, including 374 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. E928E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0081 ( 39 hom., cov: 33)

Exomes 𝑓: 0.0055 ( 335 hom. )

Consequence

IGHMBP2
NM_002180.3 missense, splice_region

Scores

Splicing: ADA: 0.7425

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 9.39

Publications

11 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0041505694).

BP6

Variant 11-68938352-G-A is Benign according to our data. Variant chr11-68938352-G-A is described in ClinVar as Benign. ClinVar VariationId is 258573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0713 is higher than 0.05.

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.2782G>A	p.Glu928Lys	missense splice_region	Exon 14 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.2782G>A	p.Glu928Lys	missense splice_region	Exon 14 of 15	ENSP00000255078.4	P38935
IGHMBP2	ENST00000544521.1	TSL:1	n.613G>A		splice_region non_coding_transcript_exon	Exon 1 of 2
IGHMBP2	ENST00000925063.1		c.2599G>A	p.Glu867Lys	missense splice_region	Exon 13 of 14	ENSP00000595122.1

Frequencies

GnomAD3 genomes

AF:

0.00808

AC:

1230

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00138

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0467

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.0776

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000529

Gnomad OTH

AF:

0.00574

GnomAD2 exomes

AF:

0.0185

AC:

4449

AN:

240642

AF XY:

0.0148

show subpopulations

Gnomad AFR exome

AF:

0.00218

Gnomad AMR exome

AF:

0.0865

Gnomad ASJ exome

AF:

0.000205

Gnomad EAS exome

AF:

0.0722

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000500

Gnomad OTH exome

AF:

0.0115

GnomAD4 exome

AF:

0.00553

AC:

8045

AN:

1455370

Hom.:

335

Cov.:

AF XY:

0.00504

AC XY:

3644

AN XY:

723652

show subpopulations

African (AFR)

AF:

0.000960

AC:

AN:

33342

American (AMR)

AF:

0.0812

AC:

3594

AN:

44236

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

26030

East Asian (EAS)

AF:

0.0872

AC:

3446

AN:

39526

South Asian (SAS)

AF:

0.00291

AC:

249

AN:

85508

European-Finnish (FIN)

AF:

0.0000192

AC:

AN:

52064

Middle Eastern (MID)

AF:

0.000875

AC:

AN:

4574

European-Non Finnish (NFE)

AF:

0.000335

AC:

372

AN:

1110014

Other (OTH)

AF:

0.00553

AC:

332

AN:

60076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

383

766

1150

1533

1916

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

118

236

354

472

590

<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:

0.00812

AC:

1237

AN:

152270

Hom.:

Cov.:

AF XY:

0.00946

AC XY:

704

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.00137

AC:

AN:

41552

American (AMR)

AF:

0.0471

AC:

721

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3468

East Asian (EAS)

AF:

0.0776

AC:

401

AN:

5170

South Asian (SAS)

AF:

0.00187

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000529

AC:

AN:

68020

Other (OTH)

AF:

0.00568

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

121

181

242

302

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00325

Hom.:

Bravo

AF:

0.0127

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00318

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.0152

AC:

1846

Asia WGS

AF:

0.0270

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (3)

Autosomal recessive distal spinal muscular atrophy 1 (1)

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

Charcot-Marie-Tooth disease (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.35

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

MetaRNN

Benign

0.0042

MetaSVM

Benign

-0.67

MutationAssessor

Pathogenic

2.9

PhyloP100

9.4

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-2.9

REVEL

Uncertain

0.42

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.014

Polyphen

1.0

Vest4

0.30

MPC

0.80

ClinPred

0.033

GERP RS

4.8

Varity_R

0.68

gMVP

0.75

Mutation Taster

=71/29

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.74

dbscSNV1_RF

Benign

0.70

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