rs554713834

chr18-31089521-C-Achr18-31089521-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024422.6(DSC2):c.548G>T(p.Arg183Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign 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. R183W) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DSC2 NM_024422.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.65

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.040557444).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSC2	NM_024422.6	c.548G>T	p.Arg183Leu	missense_variant	5/16	ENST00000280904.11
DSC2	NM_004949.5	c.548G>T	p.Arg183Leu	missense_variant	5/17
DSC2	NM_001406506.1	c.119G>T	p.Arg40Leu	missense_variant	5/16
DSC2	NM_001406507.1	c.119G>T	p.Arg40Leu	missense_variant	5/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSC2	ENST00000280904.11	c.548G>T	p.Arg183Leu	missense_variant	5/16	1	NM_024422.6	P1
DSC2	ENST00000251081.8	c.548G>T	p.Arg183Leu	missense_variant	5/17	1
DSC2	ENST00000648081.1	c.119G>T	p.Arg40Leu	missense_variant	6/17
DSC2	ENST00000682357.1	c.119G>T	p.Arg40Leu	missense_variant	5/16

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461706 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727174

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.75
Cadd	Benign	0.0010
Dann	Benign	0.34
DEOGEN2	Benign	0.039	T;.;.
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.0080	N
LIST_S2	Benign	0.25	T;T;T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.041	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.84	N;N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	2.3	N;N;.
REVEL	Benign	0.086
Sift	Benign	1.0	T;T;.
Sift4G	Benign	1.0	T;T;.
Polyphen		0.0	B;B;.
Vest4		0.12
MutPred		0.50		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;
MVP		0.19
MPC		0.091
ClinPred		0.034	T
GERP RS		-12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.16
gMVP		0.34

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: rs554713834; hg19: chr18-28669484; COSMIC: COSV51861373;