6-7574202-A-G

Variant names:

• chr6-7574202-A-G
• rs28763963
• NM_004415.4:c.2247A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_004415.4(DSP):​c.2247A>G​(p.Leu749Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000289 in 1,614,088 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L749L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00031 (8 hom.)
• Consequence: DSP NM_004415.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:6
• Conservation: PhyloP100: -0.607
• Publications: 0 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 Gene-Disease associations (from GenCC):

• keratosis palmoplantaris striata 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Genomics England PanelApp, Ambry Genetics, G2P
• arrhythmogenic cardiomyopathy with wooly hair and keratoderma

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, G2P, ClinGen
• arrhythmogenic right ventricular dysplasia 8

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• skin fragility-woolly hair-palmoplantar keratoderma syndrome

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Genomics England PanelApp, G2P, Ambry Genetics, Orphanet
• cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• dilated cardiomyopathy

  Inheritance: AD Classification: STRONG Submitted by: ClinGen
• lethal acantholytic epidermolysis bullosa

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• striate palmoplantar keratoderma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• severe dermatitis-multiple allergies-metabolic wasting syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 6-7574202-A-G is Benign according to our data. Variant chr6-7574202-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 357942.
• BP7: Synonymous conserved (PhyloP=-0.607 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000131 (20/152358) while in subpopulation EAS AF = 0.00367 (19/5184). AF 95% confidence interval is 0.0024. There are 0 homozygotes in GnomAd4. There are 9 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 8 AD,AR gene

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.2247A>G	p.Leu749Leu	synonymous	Exon 16 of 24	NP_004406.2	P15924-1
	DSP	NM_001319034.2		c.2247A>G	p.Leu749Leu	synonymous	Exon 16 of 24	NP_001305963.1	P15924-3
	DSP	NM_001008844.3		c.2247A>G	p.Leu749Leu	synonymous	Exon 16 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.2247A>G	p.Leu749Leu	synonymous	Exon 16 of 24	ENSP00000369129.3	P15924-1
	DSP	ENST00000418664.3	TSL:1	c.2247A>G	p.Leu749Leu	synonymous	Exon 16 of 24	ENSP00000396591.2	P15924-2
	DSP	ENST00000713904.1		c.2121A>G	p.Leu707Leu	synonymous	Exon 16 of 24	ENSP00000519203.1	A0AAQ5BH40

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152240 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00366

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000127 AC: 32 AN: 251274 AF XY: 0.0000883

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00174

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000306 AC: 447 AN: 1461730 Hom.: 8 Cov.: 31 AF XY: 0.000316 AC XY: 230 AN XY: 727176

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0111 AC: 442 AN: 39666

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111934

Other (OTH) AF: 0.0000497 AC: 3 AN: 60380

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152358 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74510

African (AFR) AF: 0.00 AC: 0 AN: 41586

American (AMR) AF: 0.0000653 AC: 1 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00367 AC: 19 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000430 Hom.: 0

Bravo AF: 0.0000491

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma (1)
-	1	-	Arrhythmogenic right ventricular dysplasia 8 (1)
-	-	1	Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Lethal acantholytic epidermolysis bullosa (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	1	-	Woolly hair-skin fragility syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	5.0
DANN	Benign	0.75
PhyloP100		-0.61
Mutation Taster		=100/0	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: rs28763963; hg19: chr6-7574435; COSMIC: COSV65794744;