Variant 18-30996846-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001941.5(DSC3):c.2438A>G(p.Asn813Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,866 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

DSC3
NM_001941.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.432

Variant links:

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]

DSC3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13476959).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSC3	NM_001941.5 link	c.2438A>G	p.Asn813Ser	missense_variant	15/16	ENST00000360428.9	NP_001932.2	Q14574-1
DSC3	NM_024423.4 link	c.2438A>G	p.Asn813Ser	missense_variant	15/17		NP_077741.2	Q14574-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DSC3	ENST00000360428.9 link	c.2438A>G	p.Asn813Ser	missense_variant	15/16	1	NM_001941.5	ENSP00000353608.4	Q14574-1
DSC3	ENST00000434452.5 link	c.2438A>G	p.Asn813Ser	missense_variant	15/17	5		ENSP00000392068.1	Q14574-2
DSC3	ENST00000584980.1 link	c.560A>G	p.Asn187Ser	missense_variant	4/6	5		ENSP00000464283.1	J3QRL9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727240

show subpopulations

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:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 03, 2024

The c.2438A>G (p.N813S) alteration is located in exon 15 (coding exon 15) of the DSC3 gene. This alteration results from a A to G substitution at nucleotide position 2438, causing the asparagine (N) at amino acid position 813 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.044

T;.

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.20

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.84

T;T

M_CAP

Benign

0.010

MetaRNN

Benign

0.13

T;T

MetaSVM

Benign

-0.83

MutationAssessor

Uncertain

2.4

M;M

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.034

Sift

Benign

0.42

T;T

Sift4G

Benign

0.52

T;T

Polyphen

0.12

B;B

Vest4

0.19

MutPred

0.37

Loss of sheet (P = 0.0043);Loss of sheet (P = 0.0043);

MVP

0.76

MPC

0.034

ClinPred

0.36

GERP RS

2.0

Varity_R

0.053

gMVP

0.20

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over