rs765067237

Positions:

chr18-31070731-T-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_024422.6(DSC2):c.2245A>C(p.Lys749Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,613,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

DSC2
NM_024422.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:1

Conservation

PhyloP100: 2.49

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15566844).

BS1

Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.0000178 (26/1461476) while in subpopulation AFR AF= 0.000209 (7/33456). AF 95% confidence interval is 0.0000976. There are 0 homozygotes in gnomad4_exome. There are 11 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSC2	NM_024422.6 link	c.2245A>C	p.Lys749Gln	missense_variant	14/16	ENST00000280904.11	NP_077740.1	Q02487-1
DSC2	NM_004949.5 link	c.2245A>C	p.Lys749Gln	missense_variant	14/17		NP_004940.1	Q02487-2
DSC2	NM_001406506.1 link	c.1816A>C	p.Lys606Gln	missense_variant	14/16		NP_001393435.1
DSC2	NM_001406507.1 link	c.1816A>C	p.Lys606Gln	missense_variant	14/17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DSC2	ENST00000280904.11 link	c.2245A>C	p.Lys749Gln	missense_variant	14/16	1	NM_024422.6	ENSP00000280904.6	Q02487-1
DSC2	ENST00000251081.8 link	c.2245A>C	p.Lys749Gln	missense_variant	14/17	1		ENSP00000251081.6	Q02487-2
DSC2	ENST00000648081.1 link	c.1816A>C	p.Lys606Gln	missense_variant	15/17			ENSP00000497441.1	A0A3B3ISU0
DSC2	ENST00000682357.1 link	c.1816A>C	p.Lys606Gln	missense_variant	14/16			ENSP00000507826.1	A0A3B3ISU0

Frequencies

GnomAD3 genomes

AF:

0.0000525

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251272

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135800

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000867

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1461476

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727032

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.000179

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:

0.00

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000132

Hom.:

Bravo

AF:

0.000128

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 20, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; In-silico analysis is inconclusive as to whether the variant alters gene splicing; in the absence of RNA/functional studies, the actual effect of this sequence change is unknown; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Arrhythmogenic right ventricular dysplasia 11

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 19, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 749 of the DSC2 protein (p.Lys749Gln). This variant is present in population databases (rs765067237, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with DSC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 199771). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DSC2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

May 01, 2023

This missense variant replaces lysine with glutamine at codon 749 of the DSC2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with DSC2-related disorders in the literature. This variant has been identified in 5/251272 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Familial isolated arrhythmogenic right ventricular dysplasia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Sep 23, 2024

This missense variant replaces lysine with glutamine at codon 749 of the DSC2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 5/251272 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 19, 2024

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.086

T;.;.

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.89

D;D;D

M_CAP

Benign

0.025

MetaRNN

Benign

0.16

T;T;T

MetaSVM

Benign

-0.82

MutationAssessor

Pathogenic

2.9

M;M;.

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.1

N;N;.

REVEL

Benign

0.19

Sift

Benign

0.33

T;T;.

Sift4G

Benign

0.30

T;T;.

Polyphen

0.71

P;B;.

Vest4

0.43

MVP

0.65

MPC

0.37

ClinPred

0.32

GERP RS

6.1

Varity_R

0.067

gMVP

0.56

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over