rs1238227166

Positions:

• chr6-7565500-C-G
• chr6-7565500-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_004415.4(DSP):​c.919C>G​(p.Gln307Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.77

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.

• PM1: In a repeat Spectrin 2 (size 103) in uniprot entity DESP_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_004415.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17185491).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4	c.919C>G	p.Gln307Glu	missense_variant	7/24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.919C>G	p.Gln307Glu	missense_variant	7/24		NP_001305963.1
DSP	NM_001008844.3	c.919C>G	p.Gln307Glu	missense_variant	7/24		NP_001008844.1
DSP	NM_001406591.1	c.919C>G	p.Gln307Glu	missense_variant	7/11		NP_001393520.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.919C>G	p.Gln307Glu	missense_variant	7/24	1	NM_004415.4	ENSP00000369129	P2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251212 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135760

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	0.0095	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T;.
Eigen	Benign	-0.19
Eigen_PC	Benign	0.061
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	0.96	D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.72	N;N
REVEL	Benign	0.20
Sift	Benign	0.053	T;T
Sift4G	Benign	0.27	T;T
Polyphen		0.044	B;.
Vest4		0.21
MutPred		0.29		Loss of MoRF binding (P = 0.1014);Loss of MoRF binding (P = 0.1014);
MVP		0.62
MPC		0.24
ClinPred		0.25	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.27
gMVP		0.30

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: rs1238227166; hg19: chr6-7565733; COSMIC: COSV101131734;