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rs2275996

Variant summary

Our verdict is Benign. Variant got -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. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0081 ( 39 hom., cov: 33)
Exomes 𝑓: 0.0055 ( 335 hom. )

Consequence

IGHMBP2
NM_002180.3 missense, splice_region

Scores

7
6
5
Splicing: ADA: 0.7425
2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 9.39
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]

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=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 id is 258573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68938352-G-A is described in Lovd as [Benign]. Variant chr11-68938352-G-A is described in Lovd as [Likely_benign].
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0713 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
IGHMBP2NM_002180.3 linkuse as main transcriptc.2782G>A p.Glu928Lys missense_variant, splice_region_variant 14/15 ENST00000255078.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
IGHMBP2ENST00000255078.8 linkuse as main transcriptc.2782G>A p.Glu928Lys missense_variant, splice_region_variant 14/151 NM_002180.3 P1

Frequencies

GnomAD3 genomes
AF:
0.00808
AC:
1230
AN:
152152
Hom.:
38
Cov.:
33
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
GnomAD3 exomes
AF:
0.0185
AC:
4449
AN:
240642
Hom.:
178
AF XY:
0.0148
AC XY:
1935
AN XY:
130726
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 SAS exome
AF:
0.00252
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.:
34
AF XY:
0.00504
AC XY:
3644
AN XY:
723652
show subpopulations
Gnomad4 AFR exome
AF:
0.000960
Gnomad4 AMR exome
AF:
0.0812
Gnomad4 ASJ exome
AF:
0.000576
Gnomad4 EAS exome
AF:
0.0872
Gnomad4 SAS exome
AF:
0.00291
Gnomad4 FIN exome
AF:
0.0000192
Gnomad4 NFE exome
AF:
0.000335
Gnomad4 OTH exome
AF:
0.00553
GnomAD4 genome
AF:
0.00812
AC:
1237
AN:
152270
Hom.:
39
Cov.:
33
AF XY:
0.00946
AC XY:
704
AN XY:
74450
show subpopulations
Gnomad4 AFR
AF:
0.00137
Gnomad4 AMR
AF:
0.0471
Gnomad4 ASJ
AF:
0.000288
Gnomad4 EAS
AF:
0.0776
Gnomad4 SAS
AF:
0.00187
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000529
Gnomad4 OTH
AF:
0.00568
Alfa
AF:
0.00201
Hom.:
5
Bravo
AF:
0.0127
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.00104
AC:
4
ESP6500AA
AF:
0.00318
AC:
14
ESP6500EA
AF:
0.00128
AC:
11
ExAC
AF:
0.0152
AC:
1846
Asia WGS
AF:
0.0270
AC:
94
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Likely benign, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015- -
Benign, criteria provided, single submitterclinical testingAthena Diagnostics IncSep 20, 2017- -
not specified Benign:2
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Charcot-Marie-Tooth disease Benign:1
Benign, criteria provided, single submitterclinical testingMolecular 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 submitterclinical testingInvitaeFeb 01, 2024- -
Autosomal recessive distal spinal muscular atrophy 1 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.78
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Uncertain
-0.070
Cadd
Pathogenic
33
Dann
Pathogenic
1.0
DEOGEN2
Benign
0.35
T
Eigen
Pathogenic
0.88
Eigen_PC
Pathogenic
0.80
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D
MetaRNN
Benign
0.0042
T
MetaSVM
Benign
-0.67
T
MutationAssessor
Pathogenic
2.9
M
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.70
T
PROVEAN
Uncertain
-2.9
D
REVEL
Uncertain
0.42
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.014
D
Polyphen
1.0
D
Vest4
0.30
MPC
0.80
ClinPred
0.033
T
GERP RS
4.8
Varity_R
0.68
gMVP
0.75

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs2275996; hg19: chr11-68705820; API