rs757826575

Variant names:

• chr18-31093641-G-C
• rs757826575
• NM_024422.6:c.72C>G

Your query was ambiguous. Multiple possible variants found:

• chr18-31093641-G-C
• chr18-31093641-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_024422.6(DSC2):​c.72C>G​(p.Ile24Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000667 in 149,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 1/1 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. I24V) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000067 (0 hom., cov: 32)
• Consequence: DSC2 NM_024422.6 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0490
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2793167).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSC2	NM_024422.6	c.72C>G	p.Ile24Met	missense_variant, splice_region_variant	Exon 2 of 16	ENST00000280904.11	NP_077740.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.72C>G	p.Ile24Met	missense_variant, splice_region_variant	Exon 2 of 16	1	NM_024422.6	ENSP00000280904.6

Frequencies

GnomAD3 genomes AF: 0.00000667 AC: 1 AN: 149990 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 248068 AF XY: 0.00000744

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: 0.00000890

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome AF: 0.00000667 AC: 1 AN: 149990 Hom.: 0 Cov.: 32 AF XY: 0.0000137 AC XY: 1 AN XY: 73070

African (AFR) AF: 0.00 AC: 0 AN: 40700

American (AMR) AF: 0.00 AC: 0 AN: 15034

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 5128

South Asian (SAS) AF: 0.00 AC: 0 AN: 4772

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10018

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67606

Other (OTH) AF: 0.00 AC: 0 AN: 2060

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.098	T;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.0	M;M
PhyloP100		0.049
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.19
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		0.94	P;D
Vest4		0.45
MutPred		0.46		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.49
MPC		0.17
ClinPred		0.29	T
GERP RS		-0.85
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.44
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs757826575; hg19: chr18-28673604;