18-31091132-G-A

Position:

• chr18-31091132-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000280904.11(DSC2):​c.370C>T​(p.His124Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000804 in 1,613,858 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H124R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00043 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00084 (16 hom.)
• Consequence: DSC2 ENST00000280904.11 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 1.93

Genes affected

DSC2 (HGNC:3036): (desmocollin 2) This gene encodes a member of the desmocollin protein subfamily. Desmocollins, along with desmogleins, are cadherin-like transmembrane glycoproteins that are major components of the desmosome. Desmosomes are cell-cell junctions that help resist shearing forces and are found in high concentrations in cells subject to mechanical stress. This gene is found in a cluster with other desmocollin family members on chromosome 18. Mutations in this gene are associated with arrhythmogenic right ventricular dysplasia-11, and reduced protein expression has been described in several types of cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2015]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046435595).
• BP6: Variant 18-31091132-G-A is Benign according to our data. Variant chr18-31091132-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 199781.We mark this variant Likely_benign, oryginal submissions are: {Benign=7, Uncertain_significance=1}. Variant chr18-31091132-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000427 (65/152214) while in subpopulation SAS AF= 0.0135 (65/4820). AF 95% confidence interval is 0.0109. There are 2 homozygotes in gnomad4. There are 53 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSC2	NM_024422.6	c.370C>T	p.His124Tyr	missense_variant	4/16	ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5	c.370C>T	p.His124Tyr	missense_variant	4/17		NP_004940.1
DSC2	NM_001406506.1	c.-60C>T		5_prime_UTR_variant	4/16		NP_001393435.1
DSC2	NM_001406507.1	c.-60C>T		5_prime_UTR_variant	4/17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.370C>T	p.His124Tyr	missense_variant	4/16	1	NM_024422.6	ENSP00000280904	P1
DSC2	ENST00000251081.8	c.370C>T	p.His124Tyr	missense_variant	4/17	1		ENSP00000251081
DSC2	ENST00000648081.1	c.-60C>T		5_prime_UTR_variant	5/17			ENSP00000497441
DSC2	ENST00000682357.1	c.-60C>T		5_prime_UTR_variant	4/16			ENSP00000507826

Frequencies

GnomAD3 genomes AF: 0.000427 AC: 65 AN: 152096 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0135

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00178 AC: 448 AN: 251052 Hom.: 5 AF XY: 0.00241 AC XY: 327 AN XY: 135708

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0144

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000844 AC: 1233 AN: 1461644 Hom.: 16 Cov.: 31 AF XY: 0.00121 AC XY: 881 AN XY: 727132

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0135

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.000911

GnomAD4 genome AF: 0.000427 AC: 65 AN: 152214 Hom.: 2 Cov.: 32 AF XY: 0.000712 AC XY: 53 AN XY: 74410

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0135

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000159 Hom.: 0

Bravo AF: 0.0000793

ExAC AF: 0.00199 AC: 242

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 11 Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 19, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 01, 2015	p.His124Tyr in exon 4 of DSC2: This variant is not expected to have clinical sig nificance because it has been identified in 1.4% (236/16370) of South Asian chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs371443698). -

Cardiomyopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 09, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jan 12, 2018	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 27, 2017

Variant summary: The DSC2 c.370C>T (p.His124Tyr) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 240/119242 control chromosomes (1 homozygote), predominantly observed in the South Asian subpopulation at a frequency of 0.014417 (236/16370). This frequency is about 1442 times the estimated maximal expected allele frequency of a pathogenic DSC2 variant (0.00001), suggesting this is likely a benign polymorphism found primarily in the populations of South Asian origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 26, 2017

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	13
DANN	Benign	0.82
DEOGEN2	Benign	0.37	T;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.045	N
LIST_S2	Uncertain	0.90	D;D
MetaRNN	Benign	0.0046	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.1	D;D
REVEL	Benign	0.10
Sift	Benign	0.26	T;T
Sift4G	Benign	0.17	T;D
Polyphen		0.048	B;B
Vest4		0.22
MVP		0.68
MPC		0.086
ClinPred		0.043	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.091
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: rs371443698; hg19: chr18-28671095;