NM_024422.6:c.370C>T

Variant names:

• chr18-31091132-G-A
• rs371443698
• NM_024422.6:c.370C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_024422.6(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. 14/21 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 NM_024422.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 1.93
• Publications: 1 publications found

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]

DSC2 Gene-Disease associations (from GenCC):

• arrhythmogenic right ventricular dysplasia 11

  Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• familial isolated arrhythmogenic right ventricular dysplasia

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• colorectal adenoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 199781.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD,SD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024422.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSC2	NM_024422.6	MANE Select	c.370C>T	p.His124Tyr	missense	Exon 4 of 16	NP_077740.1	Q02487-1
	DSC2	NM_004949.5		c.370C>T	p.His124Tyr	missense	Exon 4 of 17	NP_004940.1	Q02487-2
	DSC2	NM_001406506.1		c.-60C>T		5_prime_UTR	Exon 4 of 16	NP_001393435.1	A0A3B3ISU0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSC2	ENST00000280904.11	TSL:1 MANE Select	c.370C>T	p.His124Tyr	missense	Exon 4 of 16	ENSP00000280904.6	Q02487-1
	DSC2	ENST00000251081.8	TSL:1	c.370C>T	p.His124Tyr	missense	Exon 4 of 17	ENSP00000251081.6	Q02487-2
	DSC2	ENST00000713707.1		c.370C>T	p.His124Tyr	missense	Exon 4 of 16	ENSP00000519010.1	A0AAQ5BGP6

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

GnomAD2 exomes AF: 0.00178 AC: 448 AN: 251052 AF XY: 0.00241

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 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

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39690

South Asian (SAS) AF: 0.0135 AC: 1163 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111854

Other (OTH) AF: 0.000911 AC: 55 AN: 60386

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

African (AFR) AF: 0.00 AC: 0 AN: 41548

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.0135 AC: 65 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000108 Hom.: 0

Bravo AF: 0.0000793

ExAC AF: 0.00199 AC: 242

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Arrhythmogenic right ventricular dysplasia 11 (2)
-	-	2	Cardiomyopathy (2)
-	-	2	not specified (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		1.9
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.10
Sift	Benign	0.26	T
Sift4G	Benign	0.17	T
Polyphen		0.048	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
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs371443698; hg19: chr18-28671095;