11-68911494-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002180.3(IGHMBP2):ā€‹c.602T>Cā€‹(p.Leu201Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.813 in 1,613,828 control chromosomes in the GnomAD database, including 538,558 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.76 ( 45193 hom., cov: 31)
Exomes š‘“: 0.82 ( 493365 hom. )

Consequence

IGHMBP2
NM_002180.3 missense

Scores

18

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.0320
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=6.9917377E-7).
BP6
Variant 11-68911494-T-C is Benign according to our data. Variant chr11-68911494-T-C is described in ClinVar as [Benign]. Clinvar id is 258576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68911494-T-C is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.837 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
IGHMBP2NM_002180.3 linkc.602T>C p.Leu201Ser missense_variant 5/15 ENST00000255078.8 NP_002171.2 P38935
IGHMBP2XM_047426881.1 linkc.602T>C p.Leu201Ser missense_variant 5/15 XP_047282837.1
IGHMBP2XM_017017671.3 linkc.602T>C p.Leu201Ser missense_variant 5/12 XP_016873160.1
IGHMBP2XM_005273976.3 linkc.602T>C p.Leu201Ser missense_variant 5/9 XP_005274033.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
IGHMBP2ENST00000255078.8 linkc.602T>C p.Leu201Ser missense_variant 5/151 NM_002180.3 ENSP00000255078.4 P38935

Frequencies

GnomAD3 genomes
AF:
0.763
AC:
116004
AN:
151978
Hom.:
45161
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.640
Gnomad AMI
AF:
0.910
Gnomad AMR
AF:
0.828
Gnomad ASJ
AF:
0.796
Gnomad EAS
AF:
0.488
Gnomad SAS
AF:
0.729
Gnomad FIN
AF:
0.759
Gnomad MID
AF:
0.797
Gnomad NFE
AF:
0.843
Gnomad OTH
AF:
0.793
GnomAD3 exomes
AF:
0.773
AC:
194369
AN:
251366
Hom.:
76473
AF XY:
0.777
AC XY:
105609
AN XY:
135852
show subpopulations
Gnomad AFR exome
AF:
0.637
Gnomad AMR exome
AF:
0.799
Gnomad ASJ exome
AF:
0.798
Gnomad EAS exome
AF:
0.481
Gnomad SAS exome
AF:
0.742
Gnomad FIN exome
AF:
0.761
Gnomad NFE exome
AF:
0.839
Gnomad OTH exome
AF:
0.795
GnomAD4 exome
AF:
0.819
AC:
1196697
AN:
1461732
Hom.:
493365
Cov.:
49
AF XY:
0.817
AC XY:
594292
AN XY:
727172
show subpopulations
Gnomad4 AFR exome
AF:
0.637
Gnomad4 AMR exome
AF:
0.799
Gnomad4 ASJ exome
AF:
0.798
Gnomad4 EAS exome
AF:
0.531
Gnomad4 SAS exome
AF:
0.745
Gnomad4 FIN exome
AF:
0.758
Gnomad4 NFE exome
AF:
0.846
Gnomad4 OTH exome
AF:
0.788
GnomAD4 genome
AF:
0.763
AC:
116087
AN:
152096
Hom.:
45193
Cov.:
31
AF XY:
0.762
AC XY:
56642
AN XY:
74350
show subpopulations
Gnomad4 AFR
AF:
0.641
Gnomad4 AMR
AF:
0.829
Gnomad4 ASJ
AF:
0.796
Gnomad4 EAS
AF:
0.488
Gnomad4 SAS
AF:
0.728
Gnomad4 FIN
AF:
0.759
Gnomad4 NFE
AF:
0.843
Gnomad4 OTH
AF:
0.790
Alfa
AF:
0.823
Hom.:
134416
Bravo
AF:
0.762
TwinsUK
AF:
0.842
AC:
3122
ALSPAC
AF:
0.855
AC:
3297
ESP6500AA
AF:
0.650
AC:
2862
ESP6500EA
AF:
0.844
AC:
7250
ExAC
AF:
0.771
AC:
93660
Asia WGS
AF:
0.622
AC:
2165
AN:
3478
EpiCase
AF:
0.844
EpiControl
AF:
0.848

ClinVar

Significance: Benign
Submissions summary: Benign:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:5
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMar 28, 2016Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 77% of total chromosomes in ExAC -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsMay 03, 2021- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
not provided Benign:3
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 29, 2023- -
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015- -
Autosomal recessive distal spinal muscular atrophy 1 Benign:2
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. -
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
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 testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -
Charcot-Marie-Tooth disease axonal type 2S Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabAug 10, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.057
BayesDel_addAF
Benign
-0.66
T
BayesDel_noAF
Benign
-0.58
CADD
Benign
1.7
DANN
Benign
0.31
DEOGEN2
Benign
0.14
T
Eigen
Benign
-1.5
Eigen_PC
Benign
-1.4
FATHMM_MKL
Benign
0.019
N
LIST_S2
Benign
0.077
T
MetaRNN
Benign
7.0e-7
T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
0.20
N
PrimateAI
Benign
0.36
T
PROVEAN
Benign
1.9
N
REVEL
Benign
0.14
Sift
Benign
0.26
T
Sift4G
Benign
0.78
T
Polyphen
0.0
B
Vest4
0.10
MPC
0.26
ClinPred
0.012
T
GERP RS
-1.6
Varity_R
0.24
gMVP
0.30

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

LitVar

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

Other links and lift over

dbSNP: rs560096; hg19: chr11-68678962; COSMIC: COSV54822264; COSMIC: COSV54822264; API