chr6-7541997-T-C

Variant names:

• chr6-7541997-T-C
• rs766454930
• NM_004415.4:c.82T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP6

The NM_004415.4(DSP):​c.82T>C​(p.Tyr28His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,447,078 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y28D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.56
• Publications: 1 publications found

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]

DSP-AS1 (HGNC:56039): (DSP antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 6-7541997-T-C is Benign according to our data. Variant chr6-7541997-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2656209.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004415.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSP	NM_004415.4	MANE Select	c.82T>C	p.Tyr28His	missense	Exon 1 of 24	NP_004406.2	P15924-1
	DSP	NM_001319034.2		c.82T>C	p.Tyr28His	missense	Exon 1 of 24	NP_001305963.1	P15924-3
	DSP	NM_001008844.3		c.82T>C	p.Tyr28His	missense	Exon 1 of 24	NP_001008844.1	P15924-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSP	ENST00000379802.8	TSL:1 MANE Select	c.82T>C	p.Tyr28His	missense	Exon 1 of 24	ENSP00000369129.3	P15924-1
	DSP	ENST00000418664.3	TSL:1	c.82T>C	p.Tyr28His	missense	Exon 1 of 24	ENSP00000396591.2	P15924-2
	DSP	ENST00000710359.2		c.82T>C	p.Tyr28His	missense	Exon 1 of 24	ENSP00000518230.1	P15924-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000469 AC: 1 AN: 213142 AF XY: 0.00000860

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000314

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1447078 Hom.: 0 Cov.: 31 AF XY: 0.00000417 AC XY: 3 AN XY: 718608

African (AFR) AF: 0.00 AC: 0 AN: 33150

American (AMR) AF: 0.0000232 AC: 1 AN: 43018

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25796

East Asian (EAS) AF: 0.00 AC: 0 AN: 38984

South Asian (SAS) AF: 0.00 AC: 0 AN: 83642

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50800

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1106194

Other (OTH) AF: 0.00 AC: 0 AN: 59736

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Benign	0.14
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.96	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	0.69	N
PhyloP100		2.6
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.82	N
REVEL	Uncertain	0.31
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.28
MutPred		0.26		Loss of phosphorylation at Y28 (P = 0.0281)
MVP		0.64
MPC		0.42
ClinPred		0.46	T
GERP RS		3.7
PromoterAI		-0.11	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.27
gMVP		0.61
Mutation Taster		=71/29	polymorphism

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

Other links and lift over

dbSNP: rs766454930; hg19: chr6-7542230;