18-31498295-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001943.5(DSG2):ā€‹c.44T>Cā€‹(p.Leu15Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000018 in 1,111,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L15Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000018 ( 0 hom. )

Consequence

DSG2
NM_001943.5 missense, splice_region

Scores

2
6
11
Splicing: ADA: 0.007507
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.71
Variant links:
Genes affected
DSG2 (HGNC:3049): (desmoglein 2) This gene encodes a member of the desmoglein family and cadherin cell adhesion molecule superfamily of proteins. Desmogleins are calcium-binding transmembrane glycoprotein components of desmosomes, cell-cell junctions between epithelial, myocardial, and other cell types. The encoded preproprotein is proteolytically processed to generate the mature glycoprotein. This gene is present in a gene cluster with other desmoglein gene family members on chromosome 18. Mutations in this gene have been associated with arrhythmogenic right ventricular dysplasia, familial, 10. [provided by RefSeq, Jan 2016]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.814

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DSG2NM_001943.5 linkc.44T>C p.Leu15Pro missense_variant, splice_region_variant Exon 1 of 15 ENST00000261590.13 NP_001934.2 Q14126
DSG2XM_047437315.1 linkc.-529T>C splice_region_variant Exon 1 of 16 XP_047293271.1
DSG2XM_047437315.1 linkc.-529T>C 5_prime_UTR_variant Exon 1 of 16 XP_047293271.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DSG2ENST00000261590.13 linkc.44T>C p.Leu15Pro missense_variant, splice_region_variant Exon 1 of 15 1 NM_001943.5 ENSP00000261590.8 Q14126
DSG2ENST00000683654.1 linkc.44T>C p.Leu15Pro missense_variant, splice_region_variant Exon 1 of 7 ENSP00000506971.1 A0A804HIA2
DSG2ENST00000682241.2 linkc.44T>C p.Leu15Pro missense_variant, splice_region_variant Exon 1 of 7 ENSP00000507600.2 A0A804HJQ3
DSG2ENST00000585206.1 linkc.44T>C p.Leu15Pro missense_variant, splice_region_variant Exon 1 of 6 2 ENSP00000462503.1 J3KSI6

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000180
AC:
2
AN:
1111686
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
528156
show subpopulations
Gnomad4 AFR exome
AF:
0.0000425
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000107
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.40
BayesDel_addAF
Benign
-0.041
T
BayesDel_noAF
Benign
-0.30
CADD
Benign
23
DANN
Benign
0.70
DEOGEN2
Uncertain
0.57
D;T
Eigen
Benign
-0.51
Eigen_PC
Benign
-0.45
FATHMM_MKL
Benign
0.57
D
LIST_S2
Benign
0.36
T;T
M_CAP
Pathogenic
0.74
D
MetaRNN
Pathogenic
0.81
D;D
MetaSVM
Benign
-0.86
T
MutationAssessor
Benign
0.34
N;.
PrimateAI
Uncertain
0.69
T
PROVEAN
Uncertain
-2.4
N;.
REVEL
Benign
0.22
Sift
Uncertain
0.023
D;.
Sift4G
Uncertain
0.016
D;T
Polyphen
0.21
B;.
Vest4
0.53
MutPred
0.66
Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);
MVP
0.57
MPC
0.13
ClinPred
0.30
T
GERP RS
1.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.78
gMVP
0.77

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.0075
dbscSNV1_RF
Benign
0.082
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: rs372174546; hg19: chr18-29078258; API