rs568391206

chr18-31101938-C-Gchr18-31101938-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4 BP6

The NM_024422.6(DSC2):c.34G>C(p.Gly12Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000726 in 1,377,416 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Synonymous variant affecting the same amino acid position (i.e. G12G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: DSC2 NM_024422.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.0600

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]

DSCAS (HGNC:51116): (DSC1/DSC2 antisense RNA)

ACMG classification

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=0.4128907).
• BP6: Variant 18-31101938-C-G is Benign according to our data. Variant chr18-31101938-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 241473.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSC2	NM_024422.6	c.34G>C	p.Gly12Arg	missense_variant	1/16	ENST00000280904.11
DSCAS	NR_110785.1	n.136+215C>G		intron_variant, non_coding_transcript_variant
DSC2	NM_004949.5	c.34G>C	p.Gly12Arg	missense_variant	1/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSC2	ENST00000280904.11	c.34G>C	p.Gly12Arg	missense_variant	1/16	1	NM_024422.6	P1
DSCAS	ENST00000581836.2	n.152+215C>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.26e-7 AC: 1 AN: 1377416 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 679588

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: 9.30e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Feb 21, 2020

This missense variant replaces glycine with arginine at codon 12 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 been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 25351510), as well as in a healthy individual (PMID: 21636032). This variant has not been identified 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. -

Arrhythmogenic right ventricular dysplasia 11 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Oct 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	16
Dann	Uncertain	1.0
DEOGEN2	Benign	0.098	T;.
Eigen	Benign	-0.065
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.55	T;T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.41	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.2	N;N
REVEL	Uncertain	0.29
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.022	D;D
Polyphen		1.0	D;D
Vest4		0.18
MutPred		0.62		Gain of MoRF binding (P = 0.0119);Gain of MoRF binding (P = 0.0119);
MVP		0.77
MPC		0.12
ClinPred		0.39	T
GERP RS		2.6
Varity_R		0.11
gMVP		0.53

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

Other links and lift over

dbSNP: rs568391206; hg19: chr18-28681901;