rs112640831

chr6-56629273-A-Gchr6-56629273-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001374736.1(DST):c.4452T>C(p.Asn1484=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0379 in 1,613,664 control chromosomes in the GnomAD database, including 1,448 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (72 hom., cov: 32)
  • Exomes 𝑓: 0.039 (1376 hom.)
• Consequence: DST NM_001374736.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.18

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 6-56629273-A-G is Benign according to our data. Variant chr6-56629273-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 357596.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-56629273-A-G is described in Lovd as [Benign]. Variant chr6-56629273-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.17 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0247 (3757/152280) while in subpopulation NFE AF= 0.0412 (2798/67988). AF 95% confidence interval is 0.0399. There are 72 homozygotes in gnomad4. There are 1667 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 71 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DST	NM_001374736.1	c.4452T>C	p.Asn1484=	synonymous_variant	32/104	ENST00000680361.1
DST	NM_001723.7	c.2841T>C	p.Asn947=	synonymous_variant	18/24	ENST00000370765.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DST	ENST00000680361.1	c.4452T>C	p.Asn1484=	synonymous_variant	32/104		NM_001374736.1
DST	ENST00000370765.11	c.2841T>C	p.Asn947=	synonymous_variant	18/24	1	NM_001723.7

Frequencies

GnomAD3 genomes AF: 0.0247 AC: 3755 AN: 152162 Hom.: 71 Cov.: 32

Gnomad AFR AF: 0.00803

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0140

Gnomad ASJ AF: 0.0467

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0205

Gnomad FIN AF: 0.00904

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0411

Gnomad OTH AF: 0.0234

GnomAD3 exomes AF: 0.0249 AC: 6254 AN: 251358 Hom.: 113 AF XY: 0.0258 AC XY: 3503 AN XY: 135852

Gnomad AFR exome AF: 0.00757

Gnomad AMR exome AF: 0.0133

Gnomad ASJ exome AF: 0.0469

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0224

Gnomad FIN exome AF: 0.0116

Gnomad NFE exome AF: 0.0359

Gnomad OTH exome AF: 0.0289

GnomAD4 exome AF: 0.0393 AC: 57431 AN: 1461384 Hom.: 1376 Cov.: 31 AF XY: 0.0387 AC XY: 28138 AN XY: 727016

Gnomad4 AFR exome AF: 0.00619

Gnomad4 AMR exome AF: 0.0137

Gnomad4 ASJ exome AF: 0.0443

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0223

Gnomad4 FIN exome AF: 0.0128

Gnomad4 NFE exome AF: 0.0456

Gnomad4 OTH exome AF: 0.0357

GnomAD4 genome AF: 0.0247 AC: 3757 AN: 152280 Hom.: 72 Cov.: 32 AF XY: 0.0224 AC XY: 1667 AN XY: 74460

Gnomad4 AFR AF: 0.00801

Gnomad4 AMR AF: 0.0140

Gnomad4 ASJ AF: 0.0467

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0209

Gnomad4 FIN AF: 0.00904

Gnomad4 NFE AF: 0.0412

Gnomad4 OTH AF: 0.0232

Alfa AF: 0.0348 Hom.: 55

Bravo AF: 0.0242

Asia WGS AF: 0.0190 AC: 66 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary sensory and autonomic neuropathy type 6;C3809470:Epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 28, 2021

- -

Hereditary sensory and autonomic neuropathy type 6 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
Cadd	Benign	5.6
Dann	Benign	0.57

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

Publications

LitVar

Other links and lift over

dbSNP: rs112640831; hg19: chr6-56494071;