rs139350480

Variant names:

• chr6-56634196-C-T
• rs139350480
• NM_001374736.1:c.3557G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001374736.1(DST):​c.3557G>A​(p.Ser1186Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000985 in 1,613,668 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (8 hom.)
• Consequence: DST NM_001374736.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 7.91
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0101264715).
• BP6: Variant 6-56634196-C-T is Benign according to our data. Variant chr6-56634196-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 474512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00525 (800/152288) while in subpopulation AFR AF = 0.0182 (756/41546). AF 95% confidence interval is 0.0171. There are 5 homozygotes in GnomAd4. There are 377 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

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.3557G>A	p.Ser1186Asn	missense	Exon 27 of 104	NP_001361665.1	A0A7P0T890
	DST	NM_001723.7	MANE Plus Clinical	c.1946G>A	p.Ser649Asn	missense	Exon 13 of 24	NP_001714.1	Q03001-3
	DST	NM_001374734.1		c.3584G>A	p.Ser1195Asn	missense	Exon 27 of 103	NP_001361663.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DST	ENST00000680361.1	MANE Select	c.3557G>A	p.Ser1186Asn	missense	Exon 27 of 104	ENSP00000505098.1	A0A7P0T890
	DST	ENST00000370765.11	TSL:1 MANE Plus Clinical	c.1946G>A	p.Ser649Asn	missense	Exon 13 of 24	ENSP00000359801.6	Q03001-3
	DST	ENST00000244364.10	TSL:1	c.1946G>A	p.Ser649Asn	missense	Exon 13 of 84	ENSP00000244364.6	Q03001-8

Frequencies

GnomAD3 genomes AF: 0.00527 AC: 802 AN: 152170 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0183

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00138 AC: 347 AN: 251086 AF XY: 0.00108

Gnomad AFR exome AF: 0.0186

Gnomad AMR exome AF: 0.000954

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000540 AC: 789 AN: 1461380 Hom.: 8 Cov.: 32 AF XY: 0.000442 AC XY: 321 AN XY: 727016

African (AFR) AF: 0.0186 AC: 623 AN: 33476

American (AMR) AF: 0.00103 AC: 46 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52992

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000369 AC: 41 AN: 1111960

Other (OTH) AF: 0.00124 AC: 75 AN: 60392

GnomAD4 genome AF: 0.00525 AC: 800 AN: 152288 Hom.: 5 Cov.: 32 AF XY: 0.00506 AC XY: 377 AN XY: 74486

African (AFR) AF: 0.0182 AC: 756 AN: 41546

American (AMR) AF: 0.00222 AC: 34 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68024

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00174 Hom.: 14

Bravo AF: 0.00634

ESP6500AA AF: 0.0184 AC: 81

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00158 AC: 192

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

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)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.010	T
MetaSVM	Uncertain	0.45	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		7.9
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.68
MVP		0.83
MPC		0.55
ClinPred		0.035	T
GERP RS		5.0
gMVP		0.71
Mutation Taster		=88/12	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: rs139350480; hg19: chr6-56498994; COSMIC: COSV99056304; COSMIC: COSV99056304;