6-7576294-G-C

Position:

• chr6-7576294-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The ENST00000379802.8(DSP):​c.2631G>C​(p.Arg877Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R877R) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSP ENST00000379802.8 missense, splice_region
• Scores: Splicing: ADA: 0.06706
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.269

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4	c.2631G>C	p.Arg877Ser	missense_variant, splice_region_variant	19/24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.2631G>C	p.Arg877Ser	missense_variant, splice_region_variant	19/24		NP_001305963.1
DSP	NM_001008844.3	c.2631G>C	p.Arg877Ser	missense_variant, splice_region_variant	19/24		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.2631G>C	p.Arg877Ser	missense_variant, splice_region_variant	19/24	1	NM_004415.4	ENSP00000369129	P2
DSP	ENST00000418664.2	c.2631G>C	p.Arg877Ser	missense_variant, splice_region_variant	19/24	1		ENSP00000396591	A2
DSP	ENST00000710359.1	c.2631G>C	p.Arg877Ser	missense_variant, splice_region_variant	19/24			ENSP00000518230	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 43

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.33	N
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.4	M;M
MutationTaster	Benign	0.00033	P;P
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.2	D;D
REVEL	Uncertain	0.41
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.94
MutPred		0.70		Loss of MoRF binding (P = 0.0262);Loss of MoRF binding (P = 0.0262);
MVP		0.97
MPC		0.87
ClinPred		1.0	D
GERP RS		2.0
Varity_R		0.85
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.067
dbscSNV1_RF	Benign	0.31
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: rs1016835; hg19: chr6-7576527;