rs786205415

Positions:

• chr6-7577859-G-T

Variant summary

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

The ENST00000379802.8(DSP):​c.2958G>T​(p.Gln986His) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,812 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q986P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: DSP ENST00000379802.8 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.75

Genes affected

DSP (HGNC:3052): (desmoplakin) This gene encodes a protein that anchors intermediate filaments to desmosomal plaques and forms an obligate component of functional desmosomes. Mutations in this gene are the cause of several cardiomyopathies and keratodermas, including skin fragility-woolly hair syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4	c.2958G>T	p.Gln986His	missense_variant	21/24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.2958G>T	p.Gln986His	missense_variant	21/24		NP_001305963.1
DSP	NM_001008844.3	c.2958G>T	p.Gln986His	missense_variant	21/24		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.2958G>T	p.Gln986His	missense_variant	21/24	1	NM_004415.4	ENSP00000369129	P2
DSP	ENST00000418664.2	c.2958G>T	p.Gln986His	missense_variant	21/24	1		ENSP00000396591	A2
DSP	ENST00000710359.1	c.2958G>T	p.Gln986His	missense_variant	21/24			ENSP00000518230	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461812 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727214

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jun 24, 2013

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 18, 2021

The p.Q986H variant (also known as c.2958G>T), located in coding exon 21 of the DSP gene, results from a G to T substitution at nucleotide position 2958. The glutamine at codon 986 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported as a secondary cardiac variant in an exome cohort; however, clinical details are limited (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;.
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T;D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.44	T;T
MetaSVM	Uncertain	0.69	D
MutationAssessor	Benign	2.0	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;.
Vest4		0.36
MutPred		0.35		Gain of catalytic residue at S987 (P = 0.0966);Gain of catalytic residue at S987 (P = 0.0966);
MVP		0.91
MPC		0.68
ClinPred		0.98	D
GERP RS		2.7
Varity_R		0.49
gMVP		0.70

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: rs786205415; hg19: chr6-7578092;