rs4715626

Variant names:

• chr6-56517114-G-A
• rs4715626
• NM_001374736.1:c.18357+84C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-56517114-G-A
• chr6-56517114-G-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.18357+84C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.693 in 960,358 control chromosomes in the GnomAD database, including 232,386 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.66 (33426 hom., cov: 31)
  • Exomes 𝑓: 0.70 (198960 hom.)
• Consequence: DST NM_001374736.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.958
• Publications: 7 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=-0.8).
• BP6: Variant 6-56517114-G-A is Benign according to our data. Variant chr6-56517114-G-A is described in ClinVar as Benign. ClinVar VariationId is 1288855.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.699 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DST	NM_001374736.1	c.18357+84C>T		intron_variant	Intron 71 of 103	ENST00000680361.1	NP_001361665.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DST	ENST00000680361.1	c.18357+84C>T		intron_variant	Intron 71 of 103		NM_001374736.1	ENSP00000505098.1

Frequencies

GnomAD3 genomes AF: 0.658 AC: 99903 AN: 151832 Hom.: 33400 Cov.: 31

Gnomad AFR AF: 0.548

Gnomad AMI AF: 0.561

Gnomad AMR AF: 0.671

Gnomad ASJ AF: 0.561

Gnomad EAS AF: 0.664

Gnomad SAS AF: 0.655

Gnomad FIN AF: 0.818

Gnomad MID AF: 0.566

Gnomad NFE AF: 0.704

Gnomad OTH AF: 0.626

GnomAD4 exome AF: 0.699 AC: 565124 AN: 808408 Hom.: 198960 AF XY: 0.698 AC XY: 297910 AN XY: 426978

African (AFR) AF: 0.547 AC: 10726 AN: 19610

American (AMR) AF: 0.714 AC: 25981 AN: 36376

Ashkenazi Jewish (ASJ) AF: 0.572 AC: 12176 AN: 21298

East Asian (EAS) AF: 0.672 AC: 24547 AN: 36504

South Asian (SAS) AF: 0.661 AC: 44030 AN: 66622

European-Finnish (FIN) AF: 0.811 AC: 41864 AN: 51602

Middle Eastern (MID) AF: 0.618 AC: 2774 AN: 4486

European-Non Finnish (NFE) AF: 0.707 AC: 376864 AN: 532942

Other (OTH) AF: 0.671 AC: 26162 AN: 38968

GnomAD4 genome AF: 0.658 AC: 99976 AN: 151950 Hom.: 33426 Cov.: 31 AF XY: 0.662 AC XY: 49163 AN XY: 74272

African (AFR) AF: 0.548 AC: 22676 AN: 41414

American (AMR) AF: 0.672 AC: 10253 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.561 AC: 1947 AN: 3470

East Asian (EAS) AF: 0.665 AC: 3434 AN: 5164

South Asian (SAS) AF: 0.656 AC: 3152 AN: 4808

European-Finnish (FIN) AF: 0.818 AC: 8656 AN: 10580

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

European-Non Finnish (NFE) AF: 0.704 AC: 47853 AN: 67936

Other (OTH) AF: 0.629 AC: 1325 AN: 2108

Alfa AF: 0.679 Hom.: 8121

Bravo AF: 0.640

Asia WGS AF: 0.652 AC: 2269 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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.76
DANN	Benign	0.54
PhyloP100		-0.96
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: rs4715626; hg19: chr6-56381912; COSMIC: COSV107300176;