rs35497571

Positions:

• chr6-56620225-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001723.7(DST):​c.3809A>G​(p.Lys1270Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0275 in 1,613,918 control chromosomes in the GnomAD database, including 726 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (27 hom., cov: 32)
  • Exomes 𝑓: 0.028 (699 hom.)
• Consequence: DST NM_001723.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.82

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022859275).
• BP6: Variant 6-56620225-T-C is Benign according to our data. Variant chr6-56620225-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 357584.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-56620225-T-C is described in Lovd as [Benign]. Variant chr6-56620225-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0199 (3036/152356) while in subpopulation NFE AF= 0.03 (2038/68042). AF 95% confidence interval is 0.0289. There are 27 homozygotes in gnomad4. There are 1488 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 27 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DST	NM_001723.7	c.3809A>G	p.Lys1270Arg	missense_variant	23/24	ENST00000370765.11	NP_001714.1
DST	NM_001374736.1	c.4929+4305A>G		intron_variant		ENST00000680361.1	NP_001361665.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DST	ENST00000370765.11	c.3809A>G	p.Lys1270Arg	missense_variant	23/24	1	NM_001723.7	ENSP00000359801.6
DST	ENST00000680361.1	c.4929+4305A>G		intron_variant			NM_001374736.1	ENSP00000505098.1

Frequencies

GnomAD3 genomes AF: 0.0199 AC: 3036 AN: 152238 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.00516

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0135

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0130

Gnomad FIN AF: 0.0409

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0299

Gnomad OTH AF: 0.0182

GnomAD3 exomes AF: 0.0223 AC: 5584 AN: 250526 Hom.: 94 AF XY: 0.0228 AC XY: 3093 AN XY: 135490

Gnomad AFR exome AF: 0.00490

Gnomad AMR exome AF: 0.0108

Gnomad ASJ exome AF: 0.0130

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0164

Gnomad FIN exome AF: 0.0427

Gnomad NFE exome AF: 0.0304

Gnomad OTH exome AF: 0.0226

GnomAD4 exome AF: 0.0283 AC: 41313 AN: 1461562 Hom.: 699 Cov.: 34 AF XY: 0.0281 AC XY: 20408 AN XY: 727090

Gnomad4 AFR exome AF: 0.00379

Gnomad4 AMR exome AF: 0.0109

Gnomad4 ASJ exome AF: 0.0133

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0158

Gnomad4 FIN exome AF: 0.0403

Gnomad4 NFE exome AF: 0.0318

Gnomad4 OTH exome AF: 0.0244

GnomAD4 genome AF: 0.0199 AC: 3036 AN: 152356 Hom.: 27 Cov.: 32 AF XY: 0.0200 AC XY: 1488 AN XY: 74508

Gnomad4 AFR AF: 0.00517

Gnomad4 AMR AF: 0.0135

Gnomad4 ASJ AF: 0.0107

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.0130

Gnomad4 FIN AF: 0.0409

Gnomad4 NFE AF: 0.0300

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.0266 Hom.: 91

Bravo AF: 0.0171

TwinsUK AF: 0.0348 AC: 129

ALSPAC AF: 0.0330 AC: 127

ESP6500AA AF: 0.00590 AC: 26

ESP6500EA AF: 0.0278 AC: 239

ExAC AF: 0.0219 AC: 2662

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.0286

EpiControl AF: 0.0273

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 05, 2021	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hereditary sensory and autonomic neuropathy type 6 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Oct 24, 2014	- -

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	17
DANN	Uncertain	0.99
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-1.1	T
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.047
Sift	Benign	0.12	T
Sift4G	Benign	0.38	T
Polyphen		0.0010	B
Vest4		0.052
ClinPred		0.016	T
GERP RS		3.3

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: rs35497571; hg19: chr6-56485023;