18-31092107-T-G

Variant names:

• chr18-31092107-T-G
• NM_024422.6:c.348A>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024422.6(DSC2):​c.348A>C​(p.Gln116His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q116Q) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: DSC2 NM_024422.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00200

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13343093).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSC2	NM_024422.6	c.348A>C	p.Gln116His	missense_variant	Exon 3 of 16	ENST00000280904.11	NP_077740.1
DSC2	NM_004949.5	c.348A>C	p.Gln116His	missense_variant	Exon 3 of 17		NP_004940.1
DSC2	NM_001406506.1	c.-82A>C		5_prime_UTR_variant	Exon 3 of 16		NP_001393435.1
DSC2	NM_001406507.1	c.-82A>C		5_prime_UTR_variant	Exon 3 of 17		NP_001393436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSC2	ENST00000280904.11	c.348A>C	p.Gln116His	missense_variant	Exon 3 of 16	1	NM_024422.6	ENSP00000280904.6
DSC2	ENST00000251081.8	c.348A>C	p.Gln116His	missense_variant	Exon 3 of 17	1		ENSP00000251081.6
DSC2	ENST00000648081.1	c.-119A>C		5_prime_UTR_variant	Exon 3 of 17			ENSP00000497441.1
DSC2	ENST00000682357.1	c.-82A>C		5_prime_UTR_variant	Exon 3 of 16			ENSP00000507826.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459822 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726252

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.077	T;.
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.3	L;L
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.9	N;N
REVEL	Benign	0.036
Sift	Benign	0.15	T;T
Sift4G	Benign	0.18	T;T
Polyphen		0.0090	B;B
Vest4		0.27
MutPred		0.38		Loss of MoRF binding (P = 0.1064);Loss of MoRF binding (P = 0.1064);
MVP		0.54
MPC		0.076
ClinPred		0.062	T
GERP RS		-2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.059
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-28672070;