rs138553142

Variant names:

• chr6-56639604-G-C
• rs138553142
• NM_001374736.1:c.2705C>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 1P and 11B. PP3 BP4_Moderate BP6 BS1 BS2

The ENST00000680361.1(DST):​c.2705C>G​(p.Ser902Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00173 in 1,613,526 control chromosomes in the GnomAD database, including 6 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 0.0014 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (4 hom.)
• Consequence: DST ENST00000680361.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:5
• Conservation: PhyloP100: 10.0
• Publications: 2 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: Orphanet, Ambry Genetics, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency

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

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 9: BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.16644835).
• BP6: Variant 6-56639604-G-C is Benign according to our data. Variant chr6-56639604-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 474506.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00137 (208/151954) while in subpopulation NFE AF = 0.00255 (173/67948). AF 95% confidence interval is 0.00224. There are 2 homozygotes in GnomAd4. There are 88 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000680361.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DST	NM_001374736.1	MANE Select	c.2705C>G	p.Ser902Cys	missense	Exon 21 of 104	NP_001361665.1
	DST	NM_001723.7	MANE Plus Clinical	c.1094C>G	p.Ser365Cys	missense	Exon 7 of 24	NP_001714.1
	DST	NM_001374734.1		c.2732C>G	p.Ser911Cys	missense	Exon 21 of 103	NP_001361663.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DST	ENST00000680361.1	MANE Select	c.2705C>G	p.Ser902Cys	missense	Exon 21 of 104	ENSP00000505098.1
	DST	ENST00000370765.11	TSL:1 MANE Plus Clinical	c.1094C>G	p.Ser365Cys	missense	Exon 7 of 24	ENSP00000359801.6
	DST	ENST00000244364.10	TSL:1	c.1094C>G	p.Ser365Cys	missense	Exon 7 of 84	ENSP00000244364.6

Frequencies

GnomAD3 genomes AF: 0.00137 AC: 208 AN: 151836 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000363

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000919

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.000284

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00255

Gnomad OTH AF: 0.000961

GnomAD2 exomes AF: 0.00113 AC: 283 AN: 251116 AF XY: 0.00108

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000509

Gnomad NFE exome AF: 0.00223

Gnomad OTH exome AF: 0.000818

GnomAD4 exome AF: 0.00177 AC: 2590 AN: 1461572 Hom.: 4 Cov.: 32 AF XY: 0.00171 AC XY: 1240 AN XY: 727106

African (AFR) AF: 0.000269 AC: 9 AN: 33472

American (AMR) AF: 0.000157 AC: 7 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39650

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.000375 AC: 20 AN: 53374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00225 AC: 2497 AN: 1111840

Other (OTH) AF: 0.000927 AC: 56 AN: 60380

GnomAD4 genome AF: 0.00137 AC: 208 AN: 151954 Hom.: 2 Cov.: 32 AF XY: 0.00119 AC XY: 88 AN XY: 74248

African (AFR) AF: 0.000362 AC: 15 AN: 41458

American (AMR) AF: 0.000918 AC: 14 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4804

European-Finnish (FIN) AF: 0.000284 AC: 3 AN: 10548

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00255 AC: 173 AN: 67948

Other (OTH) AF: 0.000951 AC: 2 AN: 2104

Alfa AF: 0.00180 Hom.: 0

Bravo AF: 0.00115

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.00129 AC: 157

EpiCase AF: 0.00224

EpiControl AF: 0.00219

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	1	not provided (5)
-	-	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	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.17	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		10
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.73
MVP		0.91
MPC		0.56
ClinPred		0.12	T
GERP RS		5.5
gMVP		0.70
Mutation Taster		=43/57	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs138553142; hg19: chr6-56504402; COSMIC: COSV99056342; COSMIC: COSV99056342;