18-31070731-T-G

Variant names:

• chr18-31070731-T-G
• rs765067237
• NM_024422.6:c.2245A>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS1_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. 14/22 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:1
• Conservation: PhyloP100: 2.49
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• familial isolated arrhythmogenic right ventricular dysplasia

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• arrhythmogenic right ventricular dysplasia 11

  Inheritance: AR, AD, SD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• colorectal adenoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15566844).
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 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 GnomAdExome4. There are 11 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024422.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSC2	NM_024422.6	MANE Select	c.2245A>C	p.Lys749Gln	missense	Exon 14 of 16	NP_077740.1
	DSC2	NM_004949.5		c.2245A>C	p.Lys749Gln	missense	Exon 14 of 17	NP_004940.1
	DSC2	NM_001406506.1		c.1816A>C	p.Lys606Gln	missense	Exon 14 of 16	NP_001393435.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSC2	ENST00000280904.11	TSL:1 MANE Select	c.2245A>C	p.Lys749Gln	missense	Exon 14 of 16	ENSP00000280904.6
	DSC2	ENST00000251081.8	TSL:1	c.2245A>C	p.Lys749Gln	missense	Exon 14 of 17	ENSP00000251081.6
	DSC2	ENST00000713707.1		c.2266A>C	p.Lys756Gln	missense	Exon 14 of 16	ENSP00000519010.1

Frequencies

GnomAD3 genomes AF: 0.0000525 AC: 8 AN: 152236 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251272 AF XY: 0.0000221

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000178 AC: 26 AN: 1461476 Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11 AN XY: 727032

African (AFR) AF: 0.000209 AC: 7 AN: 33456

American (AMR) AF: 0.000179 AC: 8 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111768

Other (OTH) AF: 0.000182 AC: 11 AN: 60356

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74384

African (AFR) AF: 0.000169 AC: 7 AN: 41474

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000132 Hom.: 0

Bravo AF: 0.000128

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

May 20, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Clinical Genetics, Academic Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Arrhythmogenic right ventricular dysplasia 11 Uncertain:2

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.

Aug 19, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiomyopathy Uncertain:1

May 23, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Aug 19, 2024

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.086	T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		2.5
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.19
Sift	Benign	0.33	T
Sift4G	Benign	0.30	T
Polyphen		0.71	P
Vest4		0.43
MVP		0.65
MPC		0.37
ClinPred		0.32	T
GERP RS		6.1
Varity_R		0.067
gMVP		0.56
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs765067237; hg19: chr18-28650697;