18-30996796-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001941.5(DSC3):c.2488G>A(p.Gly830Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000184 in 1,613,492 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000096 (0 hom.)
• Consequence: DSC3 NM_001941.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 2.25

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.010828584).
• BP6: Variant 18-30996796-C-T is Benign according to our data. Variant chr18-30996796-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 714748.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSC3	NM_001941.5	c.2488G>A	p.Gly830Ser	missense_variant	15/16	ENST00000360428.9
DSC3	NM_024423.4	c.2488G>A	p.Gly830Ser	missense_variant	15/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSC3	ENST00000360428.9	c.2488G>A	p.Gly830Ser	missense_variant	15/16	1	NM_001941.5	P1
DSC3	ENST00000434452.5	c.2488G>A	p.Gly830Ser	missense_variant	15/17	5
DSC3	ENST00000584980.1	c.613G>A	p.Gly205Ser	missense_variant	4/6	5

Frequencies

GnomAD3 genomes AF: 0.00103 AC: 156 AN: 151962 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00346

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

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: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000311 AC: 78 AN: 250704 Hom.: 0 AF XY: 0.000221 AC XY: 30 AN XY: 135574

Gnomad AFR exome AF: 0.00425

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000442

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000965 AC: 141 AN: 1461412 Hom.: 0 Cov.: 31 AF XY: 0.0000825 AC XY: 60 AN XY: 727014

Gnomad4 AFR exome AF: 0.00314

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.000282

GnomAD4 genome AF: 0.00103 AC: 156 AN: 152080 Hom.: 0 Cov.: 32 AF XY: 0.000928 AC XY: 69 AN XY: 74344

Gnomad4 AFR AF: 0.00345

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000144 Hom.: 0

Bravo AF: 0.00124

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000338 AC: 41

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The DSC3 p.Gly830Ser variant was not identified in the literature nor was it identified in ClinVar or LOVD 3.0. The variant was identified in dbSNP (ID: rs142851621) and Cosmic (FATHMM prediction of pathogenic; score=0.74). The variant was also identified in control databases in 105 of 282074 chromosomes at a frequency of 0.000372 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 96 of 24946 chromosomes (freq: 0.003848), Other in 1 of 7214 chromosomes (freq: 0.000139), Latino in 3 of 35412 chromosomes (freq: 0.000085) and European (non-Finnish) in 5 of 128484 chromosomes (freq: 0.000039); it was not observed in the Ashkenazi Jewish, East Asian, European (Finnish) or South Asian populations. The p.Gly830 residue is not conserved in mammals and four out of five computational analyses (SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, NNSPLICE, GeneSplicer) do not predict a difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	May 16, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	22
Dann	Benign	0.91
DEOGEN2	Benign	0.12	T;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.5	L;L
MutationTaster	Benign	0.72	N;N
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Benign	0.11
Sift	Uncertain	0.011	D;D
Sift4G	Uncertain	0.012	D;D
Polyphen		0.85	P;P
Vest4		0.36
MVP		0.80
MPC		0.096
ClinPred		0.057	T
GERP RS		1.8
Varity_R		0.17
gMVP		0.35

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: rs142851621; hg19: chr18-28576762; COSMIC: COSV64573583;