18-31130647-T-G

Variant names:

• chr18-31130647-T-G
• rs879406769
• NM_024421.2:c.2552A>C

Variant summary

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

The NM_024421.2(DSC1):​c.2552A>C​(p.Asn851Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: DSC1 NM_024421.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.28

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 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=0.3203196).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSC1	NM_024421.2	c.2552A>C	p.Asn851Thr	missense_variant	Exon 16 of 16	ENST00000257198.6	NP_077739.1
DSC1	NM_004948.3	c.*75A>C		3_prime_UTR_variant	Exon 17 of 17		NP_004939.1
DSCAS	NR_110785.1	n.209-20152T>G		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSC1	ENST00000257198.6	c.2552A>C	p.Asn851Thr	missense_variant	Exon 16 of 16	2	NM_024421.2	ENSP00000257198.6
DSC1	ENST00000257197	c.*75A>C		3_prime_UTR_variant	Exon 17 of 17	1		ENSP00000257197.3
DSCAS	ENST00000654403.2	n.342T>G		non_coding_transcript_exon_variant	Exon 3 of 3
DSCAS	ENST00000581836.2	n.225-20152T>G		intron_variant	Intron 2 of 3	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.089
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.42	T
MutationAssessor	Uncertain	2.3	M
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.26
Sift	Benign	0.045	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.099	B
Vest4		0.18
MutPred		0.49		Loss of stability (P = 0.0663);
MVP		0.82
MPC		0.074
ClinPred		0.85	D
GERP RS		2.5
Varity_R		0.26
gMVP		0.32

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: rs879406769; hg19: chr18-28710610;