rs876657788

chr18-31070802-G-A

Variant summary

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

The NM_024422.6(DSC2):c.2174C>T(p.Pro725Leu) 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P725P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSC2 NM_024422.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.450

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=0.09107265).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSC2	NM_024422.6	c.2174C>T	p.Pro725Leu	missense_variant	14/16	ENST00000280904.11
DSC2	NM_004949.5	c.2174C>T	p.Pro725Leu	missense_variant	14/17
DSC2	NM_001406506.1	c.1745C>T	p.Pro582Leu	missense_variant	14/16
DSC2	NM_001406507.1	c.1745C>T	p.Pro582Leu	missense_variant	14/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSC2	ENST00000280904.11	c.2174C>T	p.Pro725Leu	missense_variant	14/16	1	NM_024422.6	P1
DSC2	ENST00000251081.8	c.2174C>T	p.Pro725Leu	missense_variant	14/17	1
DSC2	ENST00000648081.1	c.1745C>T	p.Pro582Leu	missense_variant	15/17
DSC2	ENST00000682357.1	c.1745C>T	p.Pro582Leu	missense_variant	14/16

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 28, 2015

Variant classified as Uncertain Significance - Favor Benign. The p.Pro725Leu var iant in DSC2 has not been previously reported in individuals with cardiomyopathy or in large population studies. Proline (Pro) at position 725 is not conserved in evolution, and 2 mammals (squirrel monkey and lesser Egyptian jerboa) carry a leucine (Leu) at this position, raising the possibility that this change may be tolerated. In summary, while the clinical significance of the p.Pro725Leu varia nt is uncertain, the presence of the variant amino acid in other species suggest s that it is more likely to be benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	2.4
Dann	Benign	0.65
DEOGEN2	Benign	0.084	T;.;.
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.74	T;T;T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.091	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.4	N;N;.
REVEL	Benign	0.066
Sift	Benign	0.26	T;T;.
Sift4G	Benign	0.29	T;T;.
Polyphen		0.080	B;B;.
Vest4		0.19
MutPred		0.38		Gain of sheet (P = 0.0085);Gain of sheet (P = 0.0085);.;
MVP		0.63
MPC		0.075
ClinPred		0.066	T
GERP RS		-0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.015
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

LitVar

Other links and lift over

dbSNP: rs876657788; hg19: chr18-28650768;