rs2852003

Positions:

• chr18-31032263-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001941.5(DSC3):​c.83C>A​(p.Ala28Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.057 in 1,609,726 control chromosomes in the GnomAD database, including 3,194 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.047 (245 hom., cov: 32)
  • Exomes 𝑓: 0.058 (2949 hom.)
• Consequence: DSC3 NM_001941.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.91

Genes affected

DSC3 (HGNC:3037): (desmocollin 3) 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. The desmosomal family members are arranged in two clusters on chromosome 18, occupying less than 650 kb combined. Mutations in this gene are a cause of hypotrichosis and recurrent skin vesicles disorder. The protein can act as an autoantigen in pemphigus diseases, and it is also considered to be a biomarker for some cancers. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Apr 2014]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002650261).
• BP6: Variant 18-31032263-G-T is Benign according to our data. Variant chr18-31032263-G-T is described in ClinVar as [Benign]. Clinvar id is 1268029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0626 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSC3	NM_001941.5	c.83C>A	p.Ala28Asp	missense_variant	2/16	ENST00000360428.9	NP_001932.2
DSC3	NM_024423.4	c.83C>A	p.Ala28Asp	missense_variant	2/17		NP_077741.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSC3	ENST00000360428.9	c.83C>A	p.Ala28Asp	missense_variant	2/16	1	NM_001941.5	ENSP00000353608.4
DSC3	ENST00000434452.5	c.83C>A	p.Ala28Asp	missense_variant	2/17	5		ENSP00000392068.1

Frequencies

GnomAD3 genomes AF: 0.0470 AC: 7139 AN: 151950 Hom.: 245 Cov.: 32

Gnomad AFR AF: 0.0111

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.0305

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.0386

Gnomad SAS AF: 0.0289

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0642

Gnomad OTH AF: 0.0316

GnomAD3 exomes AF: 0.0509 AC: 12780 AN: 251018 Hom.: 502 AF XY: 0.0516 AC XY: 7006 AN XY: 135762

Gnomad AFR exome AF: 0.00902

Gnomad AMR exome AF: 0.0225

Gnomad ASJ exome AF: 0.0118

Gnomad EAS exome AF: 0.0296

Gnomad SAS exome AF: 0.0269

Gnomad FIN exome AF: 0.127

Gnomad NFE exome AF: 0.0645

Gnomad OTH exome AF: 0.0485

GnomAD4 exome AF: 0.0580 AC: 84612 AN: 1457658 Hom.: 2949 Cov.: 30 AF XY: 0.0573 AC XY: 41583 AN XY: 725380

Gnomad4 AFR exome AF: 0.00816

Gnomad4 AMR exome AF: 0.0248

Gnomad4 ASJ exome AF: 0.0124

Gnomad4 EAS exome AF: 0.0404

Gnomad4 SAS exome AF: 0.0275

Gnomad4 FIN exome AF: 0.125

Gnomad4 NFE exome AF: 0.0626

Gnomad4 OTH exome AF: 0.0472

GnomAD4 genome AF: 0.0469 AC: 7139 AN: 152068 Hom.: 245 Cov.: 32 AF XY: 0.0498 AC XY: 3701 AN XY: 74354

Gnomad4 AFR AF: 0.0110

Gnomad4 AMR AF: 0.0306

Gnomad4 ASJ AF: 0.0150

Gnomad4 EAS AF: 0.0385

Gnomad4 SAS AF: 0.0289

Gnomad4 FIN AF: 0.127

Gnomad4 NFE AF: 0.0642

Gnomad4 OTH AF: 0.0313

Alfa AF: 0.0556 Hom.: 722

Bravo AF: 0.0364

TwinsUK AF: 0.0715 AC: 265

ALSPAC AF: 0.0643 AC: 248

ESP6500AA AF: 0.0109 AC: 48

ESP6500EA AF: 0.0587 AC: 505

ExAC AF: 0.0514 AC: 6237

Asia WGS AF: 0.0440 AC: 153 AN: 3476

EpiCase AF: 0.0522

EpiControl AF: 0.0536

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.076	T;.
Eigen	Benign	0.14
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.62	T;T
MetaRNN	Benign	0.0027	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M;M
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.089
Sift	Uncertain	0.0090	D;D
Sift4G	Benign	0.10	T;T
Polyphen		0.46	P;P
Vest4		0.18
MPC		0.19
ClinPred		0.024	T
GERP RS		3.5
Varity_R		0.14
gMVP		0.65

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: rs2852003; hg19: chr18-28612229; COSMIC: COSV64573246;