Variant chr18-31070728-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_024422.6(DSC2):c.2248G>C(p.Val750Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,464 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 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. V750M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

DSC2
NM_024422.6 missense, splice_region

Scores

Splicing: ADA: 0.00001851

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.286

Variant links:

Genes affected

DSC2 (HGNC:3036): (desmocollin 2) This gene encodes a member of the desmocollin protein subfamily. Desmocollins, along with desmogleins, are cadherin-like transmembrane glycoproteins that are major components of the desmosome. Desmosomes are cell-cell junctions that help resist shearing forces and are found in high concentrations in cells subject to mechanical stress. This gene is found in a cluster with other desmocollin family members on chromosome 18. Mutations in this gene are associated with arrhythmogenic right ventricular dysplasia-11, and reduced protein expression has been described in several types of cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2015]

DSC2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15437233).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
DSC2	NM_024422.6 linkuse as main transcript	c.2248G>C	p.Val750Leu	missense_variant, splice_region_variant	14/16	ENST00000280904.11
DSC2	NM_004949.5 linkuse as main transcript	c.2248G>C	p.Val750Leu	missense_variant, splice_region_variant	14/17
DSC2	NM_001406506.1 linkuse as main transcript	c.1819G>C	p.Val607Leu	missense_variant, splice_region_variant	14/16
DSC2	NM_001406507.1 linkuse as main transcript	c.1819G>C	p.Val607Leu	missense_variant, splice_region_variant	14/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSC2	ENST00000280904.11 linkuse as main transcript	c.2248G>C	p.Val750Leu	missense_variant, splice_region_variant	14/16	1	NM_024422.6	P1	Q02487-1
DSC2	ENST00000251081.8 linkuse as main transcript	c.2248G>C	p.Val750Leu	missense_variant, splice_region_variant	14/17	1			Q02487-2
DSC2	ENST00000648081.1 linkuse as main transcript	c.1819G>C	p.Val607Leu	missense_variant, splice_region_variant	15/17
DSC2	ENST00000682357.1 linkuse as main transcript	c.1819G>C	p.Val607Leu	missense_variant, splice_region_variant	14/16

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251254

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135786

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461464

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727026

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.068

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.088

T;.;.

Eigen

Benign

-0.091

Eigen_PC

Benign

-0.0057

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.85

T;T;T

M_CAP

Benign

0.042

MetaRNN

Benign

0.15

T;T;T

MetaSVM

Benign

-0.70

MutationAssessor

Uncertain

2.7

M;M;.

MutationTaster

Benign

0.84

N;N

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.4

N;N;.

REVEL

Benign

0.13

Sift

Benign

0.11

T;T;.

Sift4G

Uncertain

0.018

D;D;.

Polyphen

0.047

B;B;.

Vest4

0.19

MutPred

0.32

Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);.;

MVP

0.58

MPC

0.074

ClinPred

0.17

GERP RS

2.9

Varity_R

0.047

gMVP

0.41

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000019

dbscSNV1_RF

Benign

0.032

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over