6-7562721-G-T

Variant names:

• chr6-7562721-G-T
• rs200806163
• NM_004415.4:c.667G>T

Variant summary

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

The NM_004415.4(DSP):​c.667G>T​(p.Gly223Cys) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.30

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15567175).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSP	NM_004415.4	c.667G>T	p.Gly223Cys	missense_variant	Exon 5 of 24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.667G>T	p.Gly223Cys	missense_variant	Exon 5 of 24		NP_001305963.1
DSP	NM_001008844.3	c.667G>T	p.Gly223Cys	missense_variant	Exon 5 of 24		NP_001008844.1
DSP	NM_001406591.1	c.667G>T	p.Gly223Cys	missense_variant	Exon 5 of 11		NP_001393520.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.667G>T	p.Gly223Cys	missense_variant	Exon 5 of 24	1	NM_004415.4	ENSP00000369129.3
DSP	ENST00000418664.2	c.667G>T	p.Gly223Cys	missense_variant	Exon 5 of 24	1		ENSP00000396591.2
DSP	ENST00000710359.1	c.667G>T	p.Gly223Cys	missense_variant	Exon 5 of 24			ENSP00000518230.1
DSP	ENST00000506617.1	n.185G>T		non_coding_transcript_exon_variant	Exon 2 of 4	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiomyopathy Uncertain:1

Mar 06, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glycine with cysteine at codon 223 of the DSP protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.77	D;.
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.36	T;T
M_CAP	Benign	0.083	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	1.5	L;L
PrimateAI	Benign	0.33	T
PROVEAN	Pathogenic	-4.4	D;N
REVEL	Benign	0.17
Sift	Uncertain	0.013	D;D
Sift4G	Uncertain	0.027	D;D
Polyphen		0.21	B;.
Vest4		0.22
MutPred		0.47		Loss of disorder (P = 0.0078);Loss of disorder (P = 0.0078);
MVP		0.50
MPC		0.26
ClinPred		0.25	T
GERP RS		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.36
gMVP		0.26

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: rs200806163; hg19: chr6-7562954;