NM_024422.6:c.2103G>T

Variant names:

• chr18-31071627-C-A
• NM_024422.6:c.2103G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024422.6(DSC2):​c.2103G>T​(p.Leu701Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSC2 NM_024422.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.189

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]

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=0.2419081).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSC2	NM_024422.6	c.2103G>T	p.Leu701Phe	missense_variant	Exon 13 of 16	ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5	c.2103G>T	p.Leu701Phe	missense_variant	Exon 13 of 17		NP_004940.1
DSC2	NM_001406506.1	c.1674G>T	p.Leu558Phe	missense_variant	Exon 13 of 16		NP_001393435.1
DSC2	NM_001406507.1	c.1674G>T	p.Leu558Phe	missense_variant	Exon 13 of 17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.2103G>T	p.Leu701Phe	missense_variant	Exon 13 of 16	1	NM_024422.6	ENSP00000280904.6
DSC2	ENST00000251081.8	c.2103G>T	p.Leu701Phe	missense_variant	Exon 13 of 17	1		ENSP00000251081.6
DSC2	ENST00000648081.1	c.1674G>T	p.Leu558Phe	missense_variant	Exon 14 of 17			ENSP00000497441.1
DSC2	ENST00000682357.1	c.1674G>T	p.Leu558Phe	missense_variant	Exon 13 of 16			ENSP00000507826.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 11 Uncertain:1

Dec 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 701 of the DSC2 protein (p.Leu701Phe). This variant is not present in population databases (gnomAD no frequency). 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: 2696507). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DSC2 protein function. 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. -

Familial isolated arrhythmogenic right ventricular dysplasia Uncertain:1

Aug 15, 2023

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 leucine with phenylalanine at codon 701 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 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T;.;.
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.082
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.74	T;T;T
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Pathogenic	3.0	M;M;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.5	N;N;.
REVEL	Benign	0.19
Sift	Uncertain	0.0090	D;D;.
Sift4G	Uncertain	0.010	D;D;.
Polyphen		0.96	D;D;.
Vest4		0.32
MutPred		0.41		Loss of stability (P = 0.0895);Loss of stability (P = 0.0895);.;
MVP		0.68
MPC		0.12
ClinPred		0.92	D
GERP RS		1.4
Varity_R		0.13
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-28651593;