rs113432929

Variant names:

• chr6-56640377-T-A
• rs113432929
• NM_001374736.1:c.2256A>T

Variant summary

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

The NM_001374736.1(DST):​c.2256A>T​(p.Ser752Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0031 in 1,614,140 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (42 hom.)
• Consequence: DST NM_001374736.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: -0.268
• Publications: 3 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: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
• epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 6-56640377-T-A is Benign according to our data. Variant chr6-56640377-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 357617.
• BP7: Synonymous conserved (PhyloP=-0.268 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00265 (404/152312) while in subpopulation SAS AF = 0.0112 (54/4826). AF 95% confidence interval is 0.00881. There are 1 homozygotes in GnomAd4. There are 207 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 42 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001374736.1. 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
	DST	NM_001374736.1	MANE Select	c.2256A>T	p.Ser752Ser	synonymous	Exon 18 of 104	NP_001361665.1	A0A7P0T890
	DST	NM_001723.7	MANE Plus Clinical	c.645A>T	p.Ser215Ser	synonymous	Exon 4 of 24	NP_001714.1	Q03001-3
	DST	NM_001374734.1		c.2283A>T	p.Ser761Ser	synonymous	Exon 18 of 103	NP_001361663.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DST	ENST00000680361.1	MANE Select	c.2256A>T	p.Ser752Ser	synonymous	Exon 18 of 104	ENSP00000505098.1	A0A7P0T890
	DST	ENST00000370765.11	TSL:1 MANE Plus Clinical	c.645A>T	p.Ser215Ser	synonymous	Exon 4 of 24	ENSP00000359801.6	Q03001-3
	DST	ENST00000244364.10	TSL:1	c.645A>T	p.Ser215Ser	synonymous	Exon 4 of 84	ENSP00000244364.6	Q03001-8

Frequencies

GnomAD3 genomes AF: 0.00266 AC: 405 AN: 152194 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0112

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00331

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00411 AC: 1032 AN: 251390 AF XY: 0.00479

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00275

Gnomad ASJ exome AF: 0.0139

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00307

Gnomad OTH exome AF: 0.00554

GnomAD4 exome AF: 0.00314 AC: 4592 AN: 1461828 Hom.: 42 Cov.: 34 AF XY: 0.00354 AC XY: 2577 AN XY: 727228

African (AFR) AF: 0.000568 AC: 19 AN: 33476

American (AMR) AF: 0.00275 AC: 123 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0148 AC: 387 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0139 AC: 1196 AN: 86256

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.0147 AC: 85 AN: 5766

European-Non Finnish (NFE) AF: 0.00228 AC: 2540 AN: 1111956

Other (OTH) AF: 0.00399 AC: 241 AN: 60396

GnomAD4 genome AF: 0.00265 AC: 404 AN: 152312 Hom.: 1 Cov.: 32 AF XY: 0.00278 AC XY: 207 AN XY: 74488

African (AFR) AF: 0.000457 AC: 19 AN: 41572

American (AMR) AF: 0.00307 AC: 47 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 40 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.0112 AC: 54 AN: 4826

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.00332 AC: 226 AN: 68018

Other (OTH) AF: 0.00379 AC: 8 AN: 2110

Alfa AF: 0.00397 Hom.: 3

Bravo AF: 0.00257

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00551

EpiControl AF: 0.00492

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	1	Hereditary sensory and autonomic neuropathy type 6 (2)
-	-	2	not specified (2)
-	-	1	Hereditary sensory and autonomic neuropathy type 6;C3809470:Epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.74
DANN	Benign	0.70
PhyloP100		-0.27
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs113432929; hg19: chr6-56505175; COSMIC: COSV54995563; COSMIC: COSV54995563;