rs143342988

chr18-31068085-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 3P and 12B. PM2 PP3 BP6_Very_Strong BS1

The NM_024422.6(DSC2):c.2636A>G(p.Asp879Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000124 in 1,614,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. D879D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00081 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000052 (0 hom.)
• Consequence: DSC2 NM_024422.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 6.81

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 -9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 18-31068085-T-C is Benign according to our data. Variant chr18-31068085-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 199775.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31068085-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000815 (124/152230) while in subpopulation AFR AF= 0.00274 (114/41544). AF 95% confidence interval is 0.00233. There are 0 homozygotes in gnomad4. There are 56 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSC2	NM_024422.6	c.2636A>G	p.Asp879Gly	missense_variant	16/16	ENST00000280904.11
DSC2	NM_001406506.1	c.2207A>G	p.Asp736Gly	missense_variant	16/16
DSC2	NM_001406507.1	c.*138A>G		3_prime_UTR_variant	17/17
DSC2	NM_004949.5	c.*138A>G		3_prime_UTR_variant	17/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSC2	ENST00000280904.11	c.2636A>G	p.Asp879Gly	missense_variant	16/16	1	NM_024422.6	P1
DSC2	ENST00000251081.8	c.*138A>G		3_prime_UTR_variant	17/17	1
DSC2	ENST00000648081.1	c.2207A>G	p.Asp736Gly	missense_variant	17/17
DSC2	ENST00000682357.1	c.2207A>G	p.Asp736Gly	missense_variant	16/16

Frequencies

GnomAD3 genomes AF: 0.000828 AC: 126 AN: 152112 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00278

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000219 AC: 55 AN: 251304 Hom.: 0 AF XY: 0.0000957 AC XY: 13 AN XY: 135838

Gnomad AFR exome AF: 0.00283

Gnomad AMR exome AF: 0.000202

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: 0.00

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000520 AC: 76 AN: 1461788 Hom.: 0 Cov.: 31 AF XY: 0.0000371 AC XY: 27 AN XY: 727188

Gnomad4 AFR exome AF: 0.00182

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.000815 AC: 124 AN: 152230 Hom.: 0 Cov.: 32 AF XY: 0.000752 AC XY: 56 AN XY: 74428

Gnomad4 AFR AF: 0.00274

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000103 Hom.: 0

Bravo AF: 0.000816

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000313 AC: 38

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 16, 2015	p.Asp879Gly in exon 16 of DSC2: This variant is not expected to have clinical si gnificance because it has been identified in 0.3% (35/10398) of African chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs143342988). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 25, 2021	Variant summary: DSC2 c.2636A>G (p.Asp879Gly) results in a non-conservative amino acid change located in the Cadherin, cytoplasmic domain (IPR000233) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 252158 control chromosomes. The observed variant frequency is approximately 22 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSC2 causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.2636A>G in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and a majority consensus of likely benign (n=4). Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 16, 2020	This variant is associated with the following publications: (PMID: 21636032, 25516398, 29802319) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Arrhythmogenic right ventricular dysplasia 11 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

Cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Dec 02, 2018

- -

DSC2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 21, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 21, 2019

This alteration is classified as likely 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. -

Familial isolated arrhythmogenic right ventricular dysplasia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 05, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.14
Cadd	Pathogenic	34
Dann	Uncertain	1.0
DEOGEN2	Benign	0.30	T;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.49	T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.011	T;T
MetaSVM	Uncertain	0.080	D
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.4	D;.
REVEL	Uncertain	0.45
Sift	Uncertain	0.012	D;.
Sift4G	Uncertain	0.0060	D;.
Polyphen		0.96	D;.
Vest4		0.20
MVP		0.86
MPC		0.46
ClinPred		0.072	T
GERP RS		4.7
Varity_R		0.37
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.80		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.80		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs143342988; hg19: chr18-28648051;