18-31134631-G-C

Variant names:

• chr18-31134631-G-C
• rs748258302
• NM_024421.2:c.1817C>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_024421.2(DSC1):​c.1817C>G​(p.Pro606Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000753 in 1,460,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: DSC1 NM_024421.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.41

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.865

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSC1	NM_024421.2	c.1817C>G	p.Pro606Arg	missense_variant	Exon 12 of 16	ENST00000257198.6	NP_077739.1
DSC1	NM_004948.3	c.1817C>G	p.Pro606Arg	missense_variant	Exon 12 of 17		NP_004939.1
DSCAS	NR_110785.1	n.209-16168G>C		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSC1	ENST00000257198.6	c.1817C>G	p.Pro606Arg	missense_variant	Exon 12 of 16	2	NM_024421.2	ENSP00000257198.6
DSC1	ENST00000257197.7	c.1817C>G	p.Pro606Arg	missense_variant	Exon 12 of 17	1		ENSP00000257197.3
DSCAS	ENST00000581836.2	n.225-16168G>C		intron_variant	Intron 2 of 3	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 249838 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135056

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000299

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1460602 Hom.: 0 Cov.: 31 AF XY: 0.00000826 AC XY: 6 AN XY: 726538

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000345

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.000132 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 05, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1817C>G (p.P606R) alteration is located in exon 12 (coding exon 12) of the DSC1 gene. This alteration results from a C to G substitution at nucleotide position 1817, causing the proline (P) at amino acid position 606 to be replaced by an arginine (R). 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	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	.;T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.025	T
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Uncertain	2.4	M;M
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-7.5	D;D
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	.;D
Vest4		0.85
MutPred		0.69		Gain of catalytic residue at P606 (P = 0.04);Gain of catalytic residue at P606 (P = 0.04);
MVP		0.85
MPC		0.40
ClinPred		0.93	D
GERP RS		5.6
Varity_R		0.92
gMVP		0.88

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: rs748258302; hg19: chr18-28714594;