rs34767818

Variant names:

• chr6-56620698-C-G
• rs34767818
• NM_001723.7:c.3336G>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001723.7(DST):​c.3336G>C​(p.Glu1112Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00492 in 1,613,844 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0034 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (26 hom.)
• Consequence: DST NM_001723.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:5 B:4
• Conservation: PhyloP100: 0.498
• 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: 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006155789).
• BP6: Variant 6-56620698-C-G is Benign according to our data. Variant chr6-56620698-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 357589.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00338 (515/152286) while in subpopulation NFE AF = 0.00564 (384/68026). AF 95% confidence interval is 0.00518. There are 1 homozygotes in GnomAd4. There are 203 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 26 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001723.7. 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_001723.7	MANE Plus Clinical	c.3336G>C	p.Glu1112Asp	missense	Exon 23 of 24	NP_001714.1	Q03001-3
	DST	NM_001374736.1	MANE Select	c.4929+3832G>C		intron	N/A	NP_001361665.1	A0A7P0T890
	DST	NM_001374734.1		c.4956+3832G>C		intron	N/A	NP_001361663.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DST	ENST00000370765.11	TSL:1 MANE Plus Clinical	c.3336G>C	p.Glu1112Asp	missense	Exon 23 of 24	ENSP00000359801.6	Q03001-3
	DST	ENST00000680361.1	MANE Select	c.4929+3832G>C		intron	N/A	ENSP00000505098.1	A0A7P0T890
	DST	ENST00000244364.10	TSL:1	c.3318+3832G>C		intron	N/A	ENSP00000244364.6	Q03001-8

Frequencies

GnomAD3 genomes AF: 0.00338 AC: 514 AN: 152168 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00564

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00347 AC: 868 AN: 250036 AF XY: 0.00354

Gnomad AFR exome AF: 0.00124

Gnomad AMR exome AF: 0.00188

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000555

Gnomad NFE exome AF: 0.00607

Gnomad OTH exome AF: 0.00360

GnomAD4 exome AF: 0.00508 AC: 7428 AN: 1461558 Hom.: 26 Cov.: 33 AF XY: 0.00498 AC XY: 3619 AN XY: 727106

African (AFR) AF: 0.00105 AC: 35 AN: 33478

American (AMR) AF: 0.00197 AC: 88 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00149 AC: 39 AN: 26136

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

South Asian (SAS) AF: 0.00170 AC: 147 AN: 86254

European-Finnish (FIN) AF: 0.000713 AC: 38 AN: 53310

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5768

European-Non Finnish (NFE) AF: 0.00612 AC: 6806 AN: 1111804

Other (OTH) AF: 0.00439 AC: 265 AN: 60384

GnomAD4 genome AF: 0.00338 AC: 515 AN: 152286 Hom.: 1 Cov.: 32 AF XY: 0.00273 AC XY: 203 AN XY: 74464

African (AFR) AF: 0.00106 AC: 44 AN: 41550

American (AMR) AF: 0.00360 AC: 55 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4830

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00564 AC: 384 AN: 68026

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.00519 Hom.: 2

Bravo AF: 0.00381

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00605 AC: 52

ExAC AF: 0.00325 AC: 395

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00622

EpiControl AF: 0.00610

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	21
DANN	Uncertain	0.99
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.0062	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.50
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.070
Sift	Benign	0.45	T
Sift4G	Uncertain	0.057	T
Polyphen		0.99	D
Vest4		0.50
MutPred		0.17		Loss of methylation at K1108 (P = 0.1648)
MVP		0.38
ClinPred		0.024	T
GERP RS		4.4
Mutation Taster		=92/8	polymorphism

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: rs34767818; hg19: chr6-56485496; COSMIC: COSV55006055; COSMIC: COSV55006055;