rs751996698

Positions:

• chr18-31087690-T-A
• chr18-31087690-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_024422.6(DSC2):​c.754A>T​(p.Ile252Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DSC2 NM_024422.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0620

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36619866).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSC2	NM_024422.6	c.754A>T	p.Ile252Phe	missense_variant	6/16	ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5	c.754A>T	p.Ile252Phe	missense_variant	6/17		NP_004940.1
DSC2	NM_001406506.1	c.325A>T	p.Ile109Phe	missense_variant	6/16		NP_001393435.1
DSC2	NM_001406507.1	c.325A>T	p.Ile109Phe	missense_variant	6/17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.754A>T	p.Ile252Phe	missense_variant	6/16	1	NM_024422.6	ENSP00000280904	P1
DSC2	ENST00000251081.8	c.754A>T	p.Ile252Phe	missense_variant	6/17	1		ENSP00000251081
DSC2	ENST00000648081.1	c.325A>T	p.Ile109Phe	missense_variant	7/17			ENSP00000497441
DSC2	ENST00000682357.1	c.325A>T	p.Ile109Phe	missense_variant	6/16			ENSP00000507826

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250730 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135572

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.85e-7 AC: 1 AN: 1460696 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726704

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	13
DANN	Benign	0.94
DEOGEN2	Uncertain	0.43	T;.;.
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.79	T;T;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.37	T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.4	L;L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.4	D;D;.
REVEL	Benign	0.14
Sift	Uncertain	0.0010	D;D;.
Sift4G	Uncertain	0.036	D;D;.
Polyphen		0.011	B;B;.
Vest4		0.66
MutPred		0.74		Gain of catalytic residue at I252 (P = 0.0249);Gain of catalytic residue at I252 (P = 0.0249);.;
MVP		0.42
MPC		0.13
ClinPred		0.15	T
GERP RS		-2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.68
gMVP		0.80

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: rs751996698; hg19: chr18-28667653;