6-56501016-A-G

Variant names:

• chr6-56501016-A-G
• rs4283892
• NM_001374736.1:c.19896+64T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001374736.1(DST):​c.19896+64T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.736 in 1,495,330 control chromosomes in the GnomAD database, including 406,943 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.75 (43559 hom., cov: 32)
  • Exomes 𝑓: 0.73 (363384 hom.)
• Consequence: DST NM_001374736.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.68
• Publications: 8 publications found

Genes affected

DST (HGNC:1090): (dystonin) This gene encodes a member of the plakin protein family of adhesion junction plaque proteins. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene, but the full-length nature of some variants has not been defined. It has been reported that some isoforms are expressed in neural and muscle tissue, anchoring neural intermediate filaments to the actin cytoskeleton, and some isoforms are expressed in epithelial tissue, anchoring keratin-containing intermediate filaments to hemidesmosomes. Consistent with the expression, mice defective for this gene show skin blistering and neurodegeneration. [provided by RefSeq, Mar 2010]

DST Gene-Disease associations (from GenCC):

• hereditary sensory and autonomic neuropathy type 6

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 6-56501016-A-G is Benign according to our data. Variant chr6-56501016-A-G is described in ClinVar as Benign. ClinVar VariationId is 1288438.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.817 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DST	NM_001374736.1	c.19896+64T>C		intron_variant	Intron 80 of 103	ENST00000680361.1	NP_001361665.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DST	ENST00000680361.1	c.19896+64T>C		intron_variant	Intron 80 of 103		NM_001374736.1	ENSP00000505098.1

Frequencies

GnomAD3 genomes AF: 0.754 AC: 114547 AN: 152004 Hom.: 43513 Cov.: 32

Gnomad AFR AF: 0.824

Gnomad AMI AF: 0.558

Gnomad AMR AF: 0.698

Gnomad ASJ AF: 0.608

Gnomad EAS AF: 0.776

Gnomad SAS AF: 0.683

Gnomad FIN AF: 0.820

Gnomad MID AF: 0.566

Gnomad NFE AF: 0.729

Gnomad OTH AF: 0.692

GnomAD4 exome AF: 0.734 AC: 985892 AN: 1343208 Hom.: 363384 AF XY: 0.731 AC XY: 485957 AN XY: 664464

African (AFR) AF: 0.825 AC: 24010 AN: 29092

American (AMR) AF: 0.731 AC: 23810 AN: 32590

Ashkenazi Jewish (ASJ) AF: 0.615 AC: 14538 AN: 23640

East Asian (EAS) AF: 0.758 AC: 27297 AN: 36012

South Asian (SAS) AF: 0.681 AC: 47787 AN: 70140

European-Finnish (FIN) AF: 0.818 AC: 41631 AN: 50914

Middle Eastern (MID) AF: 0.617 AC: 3377 AN: 5476

European-Non Finnish (NFE) AF: 0.734 AC: 763422 AN: 1039630

Other (OTH) AF: 0.718 AC: 40020 AN: 55714

GnomAD4 genome AF: 0.754 AC: 114652 AN: 152122 Hom.: 43559 Cov.: 32 AF XY: 0.754 AC XY: 56035 AN XY: 74350

African (AFR) AF: 0.824 AC: 34199 AN: 41508

American (AMR) AF: 0.698 AC: 10655 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.608 AC: 2109 AN: 3470

East Asian (EAS) AF: 0.776 AC: 4020 AN: 5178

South Asian (SAS) AF: 0.684 AC: 3299 AN: 4826

European-Finnish (FIN) AF: 0.820 AC: 8689 AN: 10590

Middle Eastern (MID) AF: 0.582 AC: 171 AN: 294

European-Non Finnish (NFE) AF: 0.729 AC: 49540 AN: 67980

Other (OTH) AF: 0.693 AC: 1463 AN: 2110

Alfa AF: 0.760 Hom.: 7464

Bravo AF: 0.747

Asia WGS AF: 0.749 AC: 2604 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Mar 06, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.45
DANN	Benign	0.19
PhyloP100		-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: rs4283892; hg19: chr6-56365814; COSMIC: COSV107300173; COSMIC: COSV107300173;