rs746173561

Positions:

• chr18-31087695-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_024422.6(DSC2):​c.749T>C​(p.Phe250Ser) 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 1,460,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. F250F) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DSC2 NM_024422.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.36

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.837
• PP5: Variant 18-31087695-A-G is Pathogenic according to our data. Variant chr18-31087695-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 523128.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSC2	NM_024422.6	c.749T>C	p.Phe250Ser	missense_variant	6/16	ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5	c.749T>C	p.Phe250Ser	missense_variant	6/17		NP_004940.1
DSC2	NM_001406506.1	c.320T>C	p.Phe107Ser	missense_variant	6/16		NP_001393435.1
DSC2	NM_001406507.1	c.320T>C	p.Phe107Ser	missense_variant	6/17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.749T>C	p.Phe250Ser	missense_variant	6/16	1	NM_024422.6	ENSP00000280904.6
DSC2	ENST00000251081.8	c.749T>C	p.Phe250Ser	missense_variant	6/17	1		ENSP00000251081.6
DSC2	ENST00000648081.1	c.320T>C	p.Phe107Ser	missense_variant	7/17			ENSP00000497441.1
DSC2	ENST00000682357.1	c.320T>C	p.Phe107Ser	missense_variant	6/16			ENSP00000507826.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250810 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135626

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460932 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726796

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

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 11 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Department of Medical Bioinformatics, Sinopath Diagnosis

Mar 02, 2018

We detected the variant in two unrelated patients with ARVD11: a compound heterozygote with c.743_748delAAGTAT, and a homozygote. This variant was not detected in about 7000 individuals without any related phenotype. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Uncertain	0.099	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;.;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.71	T;T;T
M_CAP	Benign	0.061	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Uncertain	2.3	M;M;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-6.5	D;D;.
REVEL	Uncertain	0.38
Sift	Uncertain	0.0020	D;D;.
Sift4G	Uncertain	0.013	D;D;.
Polyphen		0.99	D;D;.
Vest4		0.87
MutPred		0.68		Gain of glycosylation at F250 (P = 0.0046);Gain of glycosylation at F250 (P = 0.0046);.;
MVP		0.76
MPC		0.54
ClinPred		0.95	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.75

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: rs746173561; hg19: chr18-28667658;