18-31068095-G-T

Variant names:

• chr18-31068095-G-T
• NM_024422.6:c.2626C>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_024422.6(DSC2):​c.2626C>A​(p.Gln876Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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: 5.07

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31369126).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSC2	NM_024422.6	c.2626C>A	p.Gln876Lys	missense_variant	Exon 16 of 16	ENST00000280904.11	NP_077740.1
DSC2	NM_001406506.1	c.2197C>A	p.Gln733Lys	missense_variant	Exon 16 of 16		NP_001393435.1
DSC2	NM_004949.5	c.*128C>A		3_prime_UTR_variant	Exon 17 of 17		NP_004940.1
DSC2	NM_001406507.1	c.*128C>A		3_prime_UTR_variant	Exon 17 of 17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.2626C>A	p.Gln876Lys	missense_variant	Exon 16 of 16	1	NM_024422.6	ENSP00000280904.6
DSC2	ENST00000251081	c.*128C>A		3_prime_UTR_variant	Exon 17 of 17	1		ENSP00000251081.6
DSC2	ENST00000648081.1	c.2197C>A	p.Gln733Lys	missense_variant	Exon 17 of 17			ENSP00000497441.1
DSC2	ENST00000682357.1	c.2197C>A	p.Gln733Lys	missense_variant	Exon 16 of 16			ENSP00000507826.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461814 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727208

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.082	T;.
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.31	T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.9	M;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.4	N;.
REVEL	Uncertain	0.31
Sift	Benign	0.24	T;.
Sift4G	Benign	0.15	T;.
Polyphen		0.37	B;.
Vest4		0.17
MutPred		0.33		Gain of ubiquitination at Q876 (P = 0.0048);.;
MVP		0.81
MPC		0.16
ClinPred		0.83	D
GERP RS		5.9
Varity_R		0.17
gMVP		0.49

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-28648061;