rs753775769

Variant names:

• chr18-31070728-C-G
• rs753775769
• NM_024422.6:c.2248G>C

Your query was ambiguous. Multiple possible variants found:

• chr18-31070728-C-G
• chr18-31070728-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024422.6(DSC2):​c.2248G>C​(p.Val750Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,464 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. V750M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DSC2 NM_024422.6 missense, splice_region
• Scores: Splicing: ADA: 0.00001851
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.286
• Publications: 0 publications found

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]

DSC2 Gene-Disease associations (from GenCC):

• familial isolated arrhythmogenic right ventricular dysplasia

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• arrhythmogenic right ventricular dysplasia 11

  Inheritance: AR, AD, SD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• colorectal adenoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15437233).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSC2	NM_024422.6	c.2248G>C	p.Val750Leu	missense_variant, splice_region_variant	Exon 14 of 16	ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5	c.2248G>C	p.Val750Leu	missense_variant, splice_region_variant	Exon 14 of 17		NP_004940.1
DSC2	NM_001406506.1	c.1819G>C	p.Val607Leu	missense_variant, splice_region_variant	Exon 14 of 16		NP_001393435.1
DSC2	NM_001406507.1	c.1819G>C	p.Val607Leu	missense_variant, splice_region_variant	Exon 14 of 17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.2248G>C	p.Val750Leu	missense_variant, splice_region_variant	Exon 14 of 16	1	NM_024422.6	ENSP00000280904.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251254 AF XY: 0.00000736

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461464 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727026

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111756

Other (OTH) AF: 0.00 AC: 0 AN: 60356

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.088	T;.;.
Eigen	Benign	-0.091
Eigen_PC	Benign	-0.0057
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.85	T;T;T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.7	M;M;.
PhyloP100		0.29
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.4	N;N;.
REVEL	Benign	0.13
Sift	Benign	0.11	T;T;.
Sift4G	Uncertain	0.018	D;D;.
Polyphen		0.047	B;B;.
Vest4		0.19
MutPred		0.32		Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);.;
MVP		0.58
MPC		0.074
ClinPred		0.17	T
GERP RS		2.9
Varity_R		0.047
gMVP		0.41
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000019
dbscSNV1_RF	Benign	0.032
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

Other links and lift over

dbSNP: rs753775769; hg19: chr18-28650694;