18-31134031-A-C

Position:

• chr18-31134031-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024421.2(DSC1):​c.1976T>G​(p.Met659Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00204 in 1,613,072 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (34 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (35 hom.)
• Consequence: DSC1 NM_024421.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.137

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:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046339333).
• BP6: Variant 18-31134031-A-C is Benign according to our data. Variant chr18-31134031-A-C is described in ClinVar as [Benign]. Clinvar id is 714749.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0108 (1650/152192) while in subpopulation AFR AF= 0.0374 (1555/41544). AF 95% confidence interval is 0.0359. There are 34 homozygotes in gnomad4. There are 762 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 34 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSC1	NM_024421.2	c.1976T>G	p.Met659Arg	missense_variant	13/16	ENST00000257198.6	NP_077739.1
DSC1	NM_004948.3	c.1976T>G	p.Met659Arg	missense_variant	13/17		NP_004939.1
DSCAS	NR_110785.1	n.209-16768A>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSC1	ENST00000257198.6	c.1976T>G	p.Met659Arg	missense_variant	13/16	2	NM_024421.2	ENSP00000257198.6
DSC1	ENST00000257197.7	c.1976T>G	p.Met659Arg	missense_variant	13/17	1		ENSP00000257197.3
DSCAS	ENST00000581836.2	n.225-16768A>C		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.0108 AC: 1646 AN: 152076 Hom.: 34 Cov.: 32

Gnomad AFR AF: 0.0374

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00426

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00256 AC: 641 AN: 250876 Hom.: 11 AF XY: 0.00191 AC XY: 259 AN XY: 135598

Gnomad AFR exome AF: 0.0347

Gnomad AMR exome AF: 0.00194

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: 0.0000176

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00113 AC: 1647 AN: 1460880 Hom.: 35 Cov.: 32 AF XY: 0.000977 AC XY: 710 AN XY: 726766

Gnomad4 AFR exome AF: 0.0399

Gnomad4 AMR exome AF: 0.00215

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.00312

GnomAD4 genome AF: 0.0108 AC: 1650 AN: 152192 Hom.: 34 Cov.: 32 AF XY: 0.0102 AC XY: 762 AN XY: 74418

Gnomad4 AFR AF: 0.0374

Gnomad4 AMR AF: 0.00426

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00466 Hom.: 245

Bravo AF: 0.0126

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00325 AC: 395

EpiCase AF: 0.0000546

EpiControl AF: 0.0000593

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	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 27, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	8.7
DANN	Benign	0.83
DEOGEN2	Benign	0.093	.;T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.15	T;T
MetaRNN	Benign	0.0046	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L;L
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.037
Sift	Benign	0.45	T;T
Sift4G	Benign	0.52	T;T
Polyphen		0.011	.;B
Vest4		0.26
MVP		0.68
MPC		0.099
ClinPred		0.0039	T
GERP RS		0.56
Varity_R		0.29
gMVP		0.61

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: rs28620831; hg19: chr18-28713994;