rs115542549

Positions:

• chr6-56616834-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001723.7(DST):​c.6633A>G​(p.Ala2211=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0384 in 1,614,152 control chromosomes in the GnomAD database, including 1,494 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 (76 hom., cov: 32)
  • Exomes 𝑓: 0.040 (1418 hom.)
• Consequence: DST NM_001723.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.712

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 6-56616834-T-C is Benign according to our data. Variant chr6-56616834-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 357555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-56616834-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.712 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0249 (3787/152326) while in subpopulation NFE AF= 0.0417 (2834/68026). AF 95% confidence interval is 0.0404. There are 76 homozygotes in gnomad4. There are 1679 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 76 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DST	NM_001723.7	c.6633A>G	p.Ala2211=	synonymous_variant	24/24	ENST00000370765.11
DST	NM_001374736.1	c.4930-2350A>G		intron_variant		ENST00000680361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DST	ENST00000370765.11	c.6633A>G	p.Ala2211=	synonymous_variant	24/24	1	NM_001723.7
DST	ENST00000680361.1	c.4930-2350A>G		intron_variant			NM_001374736.1

Frequencies

GnomAD3 genomes AF: 0.0249 AC: 3785 AN: 152208 Hom.: 75 Cov.: 32

Gnomad AFR AF: 0.00798

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0139

Gnomad ASJ AF: 0.0468

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0192

Gnomad FIN AF: 0.00932

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0417

Gnomad OTH AF: 0.0239

GnomAD3 exomes AF: 0.0251 AC: 6297 AN: 251198 Hom.: 114 AF XY: 0.0258 AC XY: 3506 AN XY: 135778

Gnomad AFR exome AF: 0.00759

Gnomad AMR exome AF: 0.0132

Gnomad ASJ exome AF: 0.0469

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0217

Gnomad FIN exome AF: 0.0118

Gnomad NFE exome AF: 0.0365

Gnomad OTH exome AF: 0.0293

GnomAD4 exome AF: 0.0398 AC: 58168 AN: 1461826 Hom.: 1418 Cov.: 34 AF XY: 0.0391 AC XY: 28435 AN XY: 727212

Gnomad4 AFR exome AF: 0.00636

Gnomad4 AMR exome AF: 0.0136

Gnomad4 ASJ exome AF: 0.0444

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0218

Gnomad4 FIN exome AF: 0.0133

Gnomad4 NFE exome AF: 0.0462

Gnomad4 OTH exome AF: 0.0363

GnomAD4 genome AF: 0.0249 AC: 3787 AN: 152326 Hom.: 76 Cov.: 32 AF XY: 0.0225 AC XY: 1679 AN XY: 74492

Gnomad4 AFR AF: 0.00796

Gnomad4 AMR AF: 0.0139

Gnomad4 ASJ AF: 0.0468

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0197

Gnomad4 FIN AF: 0.00932

Gnomad4 NFE AF: 0.0417

Gnomad4 OTH AF: 0.0237

Alfa AF: 0.0342 Hom.: 51

Bravo AF: 0.0244

Asia WGS AF: 0.0190 AC: 65 AN: 3478

EpiCase AF: 0.0374

EpiControl AF: 0.0362

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	-0.43
CADD	Benign	18
DANN	Benign	0.66

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: rs115542549; hg19: chr6-56481632;