18-31089581-G-T

Position:

• chr18-31089581-G-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.488C>A​(p.Thr163Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,448 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DSC2 NM_024422.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.48

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=0.25832212).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSC2	NM_024422.6	c.488C>A	p.Thr163Lys	missense_variant	5/16	ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5	c.488C>A	p.Thr163Lys	missense_variant	5/17		NP_004940.1
DSC2	NM_001406506.1	c.59C>A	p.Thr20Lys	missense_variant	5/16		NP_001393435.1
DSC2	NM_001406507.1	c.59C>A	p.Thr20Lys	missense_variant	5/17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.488C>A	p.Thr163Lys	missense_variant	5/16	1	NM_024422.6	ENSP00000280904.6
DSC2	ENST00000251081.8	c.488C>A	p.Thr163Lys	missense_variant	5/17	1		ENSP00000251081.6
DSC2	ENST00000648081.1	c.59C>A	p.Thr20Lys	missense_variant	6/17			ENSP00000497441.1
DSC2	ENST00000682357.1	c.59C>A	p.Thr20Lys	missense_variant	5/16			ENSP00000507826.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461448 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727038

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 11 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2022

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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with DSC2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 163 of the DSC2 protein (p.Thr163Lys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.040	T;.;.
Eigen	Benign	-0.17
Eigen_PC	Benign	0.023
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.58	T;T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.070	N;N;.
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-2.3	N;N;.
REVEL	Benign	0.10
Sift	Benign	0.050	D;T;.
Sift4G	Benign	0.086	T;T;.
Polyphen		0.21	B;B;.
Vest4		0.26
MutPred		0.51		Gain of ubiquitination at T163 (P = 0.0155);Gain of ubiquitination at T163 (P = 0.0155);.;
MVP		0.62
MPC		0.14
ClinPred		0.61	D
GERP RS		4.4
Varity_R		0.38
gMVP		0.41

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-28669544;