18-31134031-A-G

Variant names:

• chr18-31134031-A-G
• rs28620831
• NM_024421.2:c.1976T>C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024421.2(DSC1):​c.1976T>C​(p.Met659Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0506 in 1,613,038 control chromosomes in the GnomAD database, including 2,377 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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: 𝑓 0.036 (145 hom., cov: 32)
  • Exomes 𝑓: 0.052 (2232 hom.)
• Consequence: DSC1 NM_024421.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.137

Genes affected

DSC1 (HGNC:3035): (desmocollin 1) The protein encoded by this gene is a calcium-dependent glycoprotein that is a member of the desmocollin subfamily of the cadherin superfamily. These desmosomal family members, along with the desmogleins, are found primarily in epithelial cells where they constitute the adhesive proteins of the desmosome cell-cell junction and are required for cell adhesion and desmosome formation. A subtype of IgA pemphigus, a life-threatening autoimmune disease, is characterized by the presence of autoantibodies that target the encoded protein. The desmosomal family members are arranged in two clusters on chromosome 18. Alternative splicing of this gene results in multiple transcript variants. At least one of these variants encodes a preproprotein that is proteolytically processed to generate the mature protein. [provided by RefSeq, Nov 2015]

DSCAS (HGNC:51116): (DSC1/DSC2 antisense RNA)

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002352357).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0534 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSC1	NM_024421.2	c.1976T>C	p.Met659Thr	missense_variant	Exon 13 of 16	ENST00000257198.6	NP_077739.1
DSC1	NM_004948.3	c.1976T>C	p.Met659Thr	missense_variant	Exon 13 of 17		NP_004939.1
DSCAS	NR_110785.1	n.209-16768A>G		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSC1	ENST00000257198.6	c.1976T>C	p.Met659Thr	missense_variant	Exon 13 of 16	2	NM_024421.2	ENSP00000257198.6
DSC1	ENST00000257197.7	c.1976T>C	p.Met659Thr	missense_variant	Exon 13 of 17	1		ENSP00000257197.3
DSCAS	ENST00000581836.2	n.225-16768A>G		intron_variant	Intron 2 of 3	4

Frequencies

GnomAD3 genomes AF: 0.0357 AC: 5436 AN: 152070 Hom.: 145 Cov.: 32

Gnomad AFR AF: 0.00995

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0310

Gnomad ASJ AF: 0.0357

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0331

Gnomad FIN AF: 0.0418

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0549

Gnomad OTH AF: 0.0330

GnomAD3 exomes AF: 0.0394 AC: 9896 AN: 250876 Hom.: 279 AF XY: 0.0409 AC XY: 5544 AN XY: 135598

Gnomad AFR exome AF: 0.00745

Gnomad AMR exome AF: 0.0185

Gnomad ASJ exome AF: 0.0367

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0362

Gnomad FIN exome AF: 0.0434

Gnomad NFE exome AF: 0.0569

Gnomad OTH exome AF: 0.0436

GnomAD4 exome AF: 0.0521 AC: 76177 AN: 1460852 Hom.: 2232 Cov.: 32 AF XY: 0.0517 AC XY: 37561 AN XY: 726750

Gnomad4 AFR exome AF: 0.00795

Gnomad4 AMR exome AF: 0.0204

Gnomad4 ASJ exome AF: 0.0365

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.0356

Gnomad4 FIN exome AF: 0.0463

Gnomad4 NFE exome AF: 0.0590

Gnomad4 OTH exome AF: 0.0452

GnomAD4 genome AF: 0.0357 AC: 5436 AN: 152186 Hom.: 145 Cov.: 32 AF XY: 0.0347 AC XY: 2580 AN XY: 74418

Gnomad4 AFR AF: 0.00992

Gnomad4 AMR AF: 0.0310

Gnomad4 ASJ AF: 0.0357

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.0331

Gnomad4 FIN AF: 0.0418

Gnomad4 NFE AF: 0.0549

Gnomad4 OTH AF: 0.0327

Alfa AF: 0.0415 Hom.: 245

Bravo AF: 0.0342

TwinsUK AF: 0.0547 AC: 203

ALSPAC AF: 0.0553 AC: 213

ESP6500AA AF: 0.0109 AC: 48

ESP6500EA AF: 0.0534 AC: 459

ExAC AF: 0.0415 AC: 5032

EpiCase AF: 0.0542

EpiControl AF: 0.0541

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	2.5
DANN	Benign	0.76
DEOGEN2	Benign	0.023	.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.052	T;T
MetaRNN	Benign	0.0024	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.3	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.38	N;N
REVEL	Benign	0.077
Sift	Benign	1.0	T;T
Sift4G	Benign	0.66	T;T
Polyphen		0.0020	.;B
Vest4		0.051
MPC		0.071
ClinPred		0.0029	T
GERP RS		0.56
Varity_R		0.13
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs28620831; hg19: chr18-28713994; COSMIC: COSV57143652; COSMIC: COSV57143652;