18-31087696-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_024422.6(DSC2):c.748T>C(p.Phe250Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F250I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSC2 NM_024422.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.05

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-31087695-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 523128.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSC2	NM_024422.6	c.748T>C	p.Phe250Leu	missense_variant	6/16	ENST00000280904.11
DSC2	NM_004949.5	c.748T>C	p.Phe250Leu	missense_variant	6/17
DSC2	NM_001406506.1	c.319T>C	p.Phe107Leu	missense_variant	6/16
DSC2	NM_001406507.1	c.319T>C	p.Phe107Leu	missense_variant	6/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSC2	ENST00000280904.11	c.748T>C	p.Phe250Leu	missense_variant	6/16	1	NM_024422.6	P1
DSC2	ENST00000251081.8	c.748T>C	p.Phe250Leu	missense_variant	6/17	1
DSC2	ENST00000648081.1	c.319T>C	p.Phe107Leu	missense_variant	7/17
DSC2	ENST00000682357.1	c.319T>C	p.Phe107Leu	missense_variant	6/16

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.33	T;.;.
Eigen	Benign	-0.067
Eigen_PC	Benign	-0.042
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.64	T;T;T
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.49	T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.9	L;L;.
MutationTaster	Benign	0.61	D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-4.8	D;D;.
REVEL	Benign	0.19
Sift	Benign	0.032	D;T;.
Sift4G	Benign	0.062	T;T;.
Polyphen		0.29	B;P;.
Vest4		0.43
MutPred		0.58		Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);.;
MVP		0.66
MPC		0.10
ClinPred		0.96	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.47
gMVP		0.65

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: rs111556656; hg19: chr18-28667659;