6-7572029-A-G

Variant names:

• chr6-7572029-A-G
• rs2076304
• NM_004415.4:c.2091A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004415.4(DSP):​c.2091A>G​(p.Gly697Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.766 in 1,613,788 control chromosomes in the GnomAD database, including 475,191 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G697G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.78 (46213 hom., cov: 32)
  • Exomes 𝑓: 0.77 (428978 hom.)
• Consequence: DSP NM_004415.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:13
• Conservation: PhyloP100: -0.844
• Publications: 23 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 6-7572029-A-G is Benign according to our data. Variant chr6-7572029-A-G is described in ClinVar as Benign. ClinVar VariationId is 44870.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.844 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.793 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.2091A>G	p.Gly697Gly	synonymous	Exon 15 of 24	NP_004406.2	P15924-1
	DSP	NM_001319034.2		c.2091A>G	p.Gly697Gly	synonymous	Exon 15 of 24	NP_001305963.1	P15924-3
	DSP	NM_001008844.3		c.2091A>G	p.Gly697Gly	synonymous	Exon 15 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.2091A>G	p.Gly697Gly	synonymous	Exon 15 of 24	ENSP00000369129.3	P15924-1
	DSP	ENST00000418664.3	TSL:1	c.2091A>G	p.Gly697Gly	synonymous	Exon 15 of 24	ENSP00000396591.2	P15924-2
	DSP	ENST00000713904.1		c.1965A>G	p.Gly655Gly	synonymous	Exon 15 of 24	ENSP00000519203.1	A0AAQ5BH40

Frequencies

GnomAD3 genomes AF: 0.778 AC: 118340 AN: 152014 Hom.: 46193 Cov.: 32

Gnomad AFR AF: 0.800

Gnomad AMI AF: 0.784

Gnomad AMR AF: 0.789

Gnomad ASJ AF: 0.844

Gnomad EAS AF: 0.814

Gnomad SAS AF: 0.688

Gnomad FIN AF: 0.719

Gnomad MID AF: 0.810

Gnomad NFE AF: 0.773

Gnomad OTH AF: 0.784

GnomAD2 exomes AF: 0.763 AC: 191399 AN: 250974 AF XY: 0.758

Gnomad AFR exome AF: 0.802

Gnomad AMR exome AF: 0.771

Gnomad ASJ exome AF: 0.835

Gnomad EAS exome AF: 0.807

Gnomad FIN exome AF: 0.717

Gnomad NFE exome AF: 0.771

Gnomad OTH exome AF: 0.771

GnomAD4 exome AF: 0.765 AC: 1118428 AN: 1461656 Hom.: 428978 Cov.: 59 AF XY: 0.764 AC XY: 555190 AN XY: 727130

African (AFR) AF: 0.798 AC: 26728 AN: 33474

American (AMR) AF: 0.775 AC: 34673 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.835 AC: 21830 AN: 26136

East Asian (EAS) AF: 0.837 AC: 33218 AN: 39700

South Asian (SAS) AF: 0.686 AC: 59134 AN: 86244

European-Finnish (FIN) AF: 0.715 AC: 38169 AN: 53408

Middle Eastern (MID) AF: 0.778 AC: 4487 AN: 5764

European-Non Finnish (NFE) AF: 0.767 AC: 853330 AN: 1111830

Other (OTH) AF: 0.776 AC: 46859 AN: 60388

GnomAD4 genome AF: 0.778 AC: 118405 AN: 152132 Hom.: 46213 Cov.: 32 AF XY: 0.776 AC XY: 57701 AN XY: 74370

African (AFR) AF: 0.799 AC: 33151 AN: 41494

American (AMR) AF: 0.789 AC: 12071 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.844 AC: 2932 AN: 3472

East Asian (EAS) AF: 0.813 AC: 4207 AN: 5172

South Asian (SAS) AF: 0.689 AC: 3316 AN: 4816

European-Finnish (FIN) AF: 0.719 AC: 7611 AN: 10582

Middle Eastern (MID) AF: 0.810 AC: 238 AN: 294

European-Non Finnish (NFE) AF: 0.773 AC: 52519 AN: 67980

Other (OTH) AF: 0.781 AC: 1647 AN: 2110

Alfa AF: 0.775 Hom.: 34554

Bravo AF: 0.789

Asia WGS AF: 0.700 AC: 2434 AN: 3478

EpiCase AF: 0.795

EpiControl AF: 0.778

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	1	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma (1)
-	-	1	Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Keratosis palmoplantaris striata 2 (1)
-	-	1	Lethal acantholytic epidermolysis bullosa (1)
-	1	-	not provided (1)
-	-	1	Woolly hair-skin fragility syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.1
DANN	Benign	0.55
PhyloP100		-0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs2076304; hg19: chr6-7572262; COSMIC: COSV65791873;