rs371741067

Variant names:

• chr6-56625198-G-A
• rs371741067
• NM_001374736.1:c.4789C>T
• DST p.Arg1597Cys

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001374736.1(DST):​c.4789C>T​(p.Arg1597Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000818 in 1,613,196 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000088 (1 hom.)
• Consequence: DST NM_001374736.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 5.21
• 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: 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: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001374736.1. 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_001374736.1	MANE Select	c.4789C>T	p.Arg1597Cys	missense	Exon 35 of 104	NP_001361665.1	A0A7P0T890
	DST	NM_001723.7	MANE Plus Clinical	c.3178C>T	p.Arg1060Cys	missense	Exon 21 of 24	NP_001714.1	Q03001-3
	DST	NM_001374734.1		c.4816C>T	p.Arg1606Cys	missense	Exon 35 of 103	NP_001361663.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DST	ENST00000680361.1	MANE Select	c.4789C>T	p.Arg1597Cys	missense	Exon 35 of 104	ENSP00000505098.1	A0A7P0T890
	DST	ENST00000370765.11	TSL:1 MANE Plus Clinical	c.3178C>T	p.Arg1060Cys	missense	Exon 21 of 24	ENSP00000359801.6	Q03001-3
	DST	ENST00000244364.10	TSL:1	c.3178C>T	p.Arg1060Cys	missense	Exon 21 of 84	ENSP00000244364.6	Q03001-8

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 151970 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000438 AC: 11 AN: 251412 AF XY: 0.0000294

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000883 AC: 129 AN: 1461226 Hom.: 1 Cov.: 30 AF XY: 0.0000963 AC XY: 70 AN XY: 726954

African (AFR) AF: 0.0000299 AC: 1 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.000303 AC: 12 AN: 39640

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000101 AC: 112 AN: 1111538

Other (OTH) AF: 0.0000331 AC: 2 AN: 60366

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 151970 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74210

African (AFR) AF: 0.0000242 AC: 1 AN: 41366

American (AMR) AF: 0.00 AC: 0 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67984

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Hereditary sensory and autonomic neuropathy type 6;C3809470:Epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.0037	T
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.37	T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Benign	0.070	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.2
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-6.7	D
REVEL	Benign	0.26
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.28
Mutation Taster		=49/51	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs371741067; hg19: chr6-56489996; COSMIC: COSV55002725;