rs556292818

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_002180.3(IGHMBP2):​c.1516G>A​(p.Glu506Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000877 in 1,596,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E506E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

IGHMBP2
NM_002180.3 missense

Scores

1
7
11

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.97
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 Uncertain_significance. Variant got 2 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_002180.3
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.2197878).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
IGHMBP2NM_002180.3 linkuse as main transcriptc.1516G>A p.Glu506Lys missense_variant 10/15 ENST00000255078.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
IGHMBP2ENST00000255078.8 linkuse as main transcriptc.1516G>A p.Glu506Lys missense_variant 10/151 NM_002180.3 P1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152212
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000137
AC:
3
AN:
218192
Hom.:
0
AF XY:
0.00000848
AC XY:
1
AN XY:
117946
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000121
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000105
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000692
AC:
10
AN:
1444208
Hom.:
0
Cov.:
31
AF XY:
0.00000698
AC XY:
5
AN XY:
716844
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000255
Gnomad4 SAS exome
AF:
0.0000119
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000635
Gnomad4 OTH exome
AF:
0.0000168
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152330
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74486
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000301
Hom.:
0
Bravo
AF:
0.0000113
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.011
T
BayesDel_noAF
Benign
-0.25
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.51
D
Eigen
Benign
-0.24
Eigen_PC
Benign
-0.26
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.94
D
M_CAP
Uncertain
0.088
D
MetaRNN
Benign
0.22
T
MetaSVM
Uncertain
-0.12
T
MutationAssessor
Benign
1.3
L
MutationTaster
Benign
0.99
D
PrimateAI
Benign
0.42
T
PROVEAN
Uncertain
-2.6
D
REVEL
Uncertain
0.33
Sift
Benign
0.040
D
Sift4G
Benign
0.086
T
Polyphen
0.44
B
Vest4
0.32
MVP
0.87
MPC
0.64
ClinPred
0.96
D
GERP RS
3.7
Varity_R
0.33
gMVP
0.60

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: rs556292818; hg19: chr11-68701360; COSMIC: COSV54824647; COSMIC: COSV54824647; API