chr6-7585734-G-C

Variant names:

• chr6-7585734-G-C
• rs2744380
• NM_004415.4:c.8472G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_004415.4(DSP):​c.8472G>C​(p.Gly2824Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.701 in 1,611,304 control chromosomes in the GnomAD database, including 397,692 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. G2824G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.69 (36549 hom., cov: 32)
  • Exomes 𝑓: 0.70 (361143 hom.)
• Consequence: DSP NM_004415.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:25
• Conservation: PhyloP100: -0.0450
• Publications: 16 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=-0.65).
• BP6: Variant 6-7585734-G-C is Benign according to our data. Variant chr6-7585734-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 44967.
• BP7: Synonymous conserved (PhyloP=-0.045 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.776 is higher than 0.05.

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.8472G>C	p.Gly2824Gly	synonymous	Exon 24 of 24	NP_004406.2	P15924-1
	DSP	NM_001319034.2		c.7143G>C	p.Gly2381Gly	synonymous	Exon 24 of 24	NP_001305963.1	P15924-3
	DSP	NM_001008844.3		c.6675G>C	p.Gly2225Gly	synonymous	Exon 24 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.8472G>C	p.Gly2824Gly	synonymous	Exon 24 of 24	ENSP00000369129.3	P15924-1
	DSP	ENST00000418664.3	TSL:1	c.6675G>C	p.Gly2225Gly	synonymous	Exon 24 of 24	ENSP00000396591.2	P15924-2
	DSP	ENST00000713904.1		c.8346G>C	p.Gly2782Gly	synonymous	Exon 24 of 24	ENSP00000519203.1	A0AAQ5BH40

Frequencies

GnomAD3 genomes AF: 0.691 AC: 104985 AN: 151956 Hom.: 36528 Cov.: 32

Gnomad AFR AF: 0.638

Gnomad AMI AF: 0.694

Gnomad AMR AF: 0.755

Gnomad ASJ AF: 0.752

Gnomad EAS AF: 0.796

Gnomad SAS AF: 0.725

Gnomad FIN AF: 0.649

Gnomad MID AF: 0.785

Gnomad NFE AF: 0.700

Gnomad OTH AF: 0.711

GnomAD2 exomes AF: 0.714 AC: 177513 AN: 248526 AF XY: 0.715

Gnomad AFR exome AF: 0.636

Gnomad AMR exome AF: 0.750

Gnomad ASJ exome AF: 0.745

Gnomad EAS exome AF: 0.804

Gnomad FIN exome AF: 0.647

Gnomad NFE exome AF: 0.709

Gnomad OTH exome AF: 0.707

GnomAD4 exome AF: 0.703 AC: 1025199 AN: 1459228 Hom.: 361143 Cov.: 84 AF XY: 0.704 AC XY: 510788 AN XY: 725680

African (AFR) AF: 0.629 AC: 20962 AN: 33314

American (AMR) AF: 0.752 AC: 33360 AN: 44342

Ashkenazi Jewish (ASJ) AF: 0.746 AC: 19416 AN: 26034

East Asian (EAS) AF: 0.814 AC: 32299 AN: 39674

South Asian (SAS) AF: 0.722 AC: 62095 AN: 86026

European-Finnish (FIN) AF: 0.646 AC: 34462 AN: 53326

Middle Eastern (MID) AF: 0.757 AC: 4345 AN: 5742

European-Non Finnish (NFE) AF: 0.698 AC: 775447 AN: 1110524

Other (OTH) AF: 0.711 AC: 42813 AN: 60246

GnomAD4 genome AF: 0.691 AC: 105059 AN: 152076 Hom.: 36549 Cov.: 32 AF XY: 0.694 AC XY: 51573 AN XY: 74336

African (AFR) AF: 0.638 AC: 26467 AN: 41458

American (AMR) AF: 0.755 AC: 11548 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.752 AC: 2611 AN: 3470

East Asian (EAS) AF: 0.796 AC: 4106 AN: 5156

South Asian (SAS) AF: 0.725 AC: 3497 AN: 4822

European-Finnish (FIN) AF: 0.649 AC: 6872 AN: 10584

Middle Eastern (MID) AF: 0.799 AC: 235 AN: 294

European-Non Finnish (NFE) AF: 0.700 AC: 47595 AN: 67980

Other (OTH) AF: 0.708 AC: 1495 AN: 2112

Alfa AF: 0.697 Hom.: 11999

Bravo AF: 0.697

EpiCase AF: 0.728

EpiControl AF: 0.717

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	1	2	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma (3)
-	-	2	Arrhythmogenic right ventricular dysplasia 8 (2)
-	-	2	Cardiomyopathy (2)
-	-	2	Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis (2)
-	-	2	Lethal acantholytic epidermolysis bullosa (2)
-	-	2	Woolly hair-skin fragility syndrome (2)
-	-	1	Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	DSP-related disorder (1)
-	-	1	Keratosis palmoplantaris striata 2 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	2.5
DANN	Benign	0.70
PhyloP100		-0.045
Mutation Taster		=100/0	polymorphism (auto)

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: rs2744380; hg19: chr6-7585967; COSMIC: COSV60939587; COSMIC: COSV60939587;