18-31074784-G-C

Position:

• chr18-31074784-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_024422.6(DSC2):​c.1787C>G​(p.Ala596Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. A596V) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: DSC2 NM_024422.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.44

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.848

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSC2	NM_024422.6	c.1787C>G	p.Ala596Gly	missense_variant	12/16	ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5	c.1787C>G	p.Ala596Gly	missense_variant	12/17		NP_004940.1
DSC2	NM_001406506.1	c.1358C>G	p.Ala453Gly	missense_variant	12/16		NP_001393435.1
DSC2	NM_001406507.1	c.1358C>G	p.Ala453Gly	missense_variant	12/17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.1787C>G	p.Ala596Gly	missense_variant	12/16	1	NM_024422.6	ENSP00000280904.6
DSC2	ENST00000251081.8	c.1787C>G	p.Ala596Gly	missense_variant	12/17	1		ENSP00000251081.6
DSC2	ENST00000648081.1	c.1358C>G	p.Ala453Gly	missense_variant	13/17			ENSP00000497441.1
DSC2	ENST00000682357.1	c.1358C>G	p.Ala453Gly	missense_variant	12/16			ENSP00000507826.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251052 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135680

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: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461760 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727166

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;.;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Uncertain	0.097	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Pathogenic	3.5	M;M;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.9	D;D;.
REVEL	Uncertain	0.53
Sift	Benign	0.046	D;D;.
Sift4G	Benign	0.076	T;T;.
Polyphen		0.95	P;D;.
Vest4		0.71
MutPred		0.67		Gain of disorder (P = 0.1019);Gain of disorder (P = 0.1019);.;
MVP		0.87
MPC		0.30
ClinPred		0.95	D
GERP RS		5.3
Varity_R		0.37
gMVP		0.85

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: rs148185335; hg19: chr18-28654750;