rs35014998

Variant names:

• chr6-56628047-A-C
• rs35014998
• NM_001374736.1:c.4590T>G

Your query was ambiguous. Multiple possible variants found:

• chr6-56628047-A-C
• chr6-56628047-A-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001374736.1(DST):​c.4590T>G​(p.Asn1530Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00439 in 1,613,758 control chromosomes in the GnomAD database, including 224 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (109 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (115 hom.)
• Consequence: DST NM_001374736.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.78
• Publications: 4 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: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Orphanet, G2P
• epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001757592).
• BP6: Variant 6-56628047-A-C is Benign according to our data. Variant chr6-56628047-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 357595.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0744 is higher than 0.05.

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.4590T>G	p.Asn1530Lys	missense	Exon 33 of 104	NP_001361665.1	A0A7P0T890
	DST	NM_001723.7	MANE Plus Clinical	c.2979T>G	p.Asn993Lys	missense	Exon 19 of 24	NP_001714.1	Q03001-3
	DST	NM_001374734.1		c.4617T>G	p.Asn1539Lys	missense	Exon 33 of 103	NP_001361663.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DST	ENST00000680361.1	MANE Select	c.4590T>G	p.Asn1530Lys	missense	Exon 33 of 104	ENSP00000505098.1	A0A7P0T890
	DST	ENST00000370765.11	TSL:1 MANE Plus Clinical	c.2979T>G	p.Asn993Lys	missense	Exon 19 of 24	ENSP00000359801.6	Q03001-3
	DST	ENST00000244364.10	TSL:1	c.2979T>G	p.Asn993Lys	missense	Exon 19 of 84	ENSP00000244364.6	Q03001-8

Frequencies

GnomAD3 genomes AF: 0.0220 AC: 3351 AN: 151976 Hom.: 106 Cov.: 32

Gnomad AFR AF: 0.0763

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00859

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.0158

GnomAD2 exomes AF: 0.00616 AC: 1548 AN: 251370 AF XY: 0.00458

Gnomad AFR exome AF: 0.0826

Gnomad AMR exome AF: 0.00385

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000431

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00254 AC: 3716 AN: 1461664 Hom.: 115 Cov.: 31 AF XY: 0.00225 AC XY: 1637 AN XY: 727146

African (AFR) AF: 0.0796 AC: 2664 AN: 33454

American (AMR) AF: 0.00487 AC: 218 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5768

European-Non Finnish (NFE) AF: 0.000460 AC: 511 AN: 1111840

Other (OTH) AF: 0.00492 AC: 297 AN: 60390

GnomAD4 genome AF: 0.0222 AC: 3373 AN: 152094 Hom.: 109 Cov.: 32 AF XY: 0.0221 AC XY: 1644 AN XY: 74354

African (AFR) AF: 0.0766 AC: 3176 AN: 41460

American (AMR) AF: 0.00858 AC: 131 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

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

European-Non Finnish (NFE) AF: 0.000485 AC: 33 AN: 67994

Other (OTH) AF: 0.0156 AC: 33 AN: 2114

Alfa AF: 0.00707 Hom.: 77

Bravo AF: 0.0253

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0781 AC: 344

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00708 AC: 860

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000415

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	DST-related disorder (1)
-	-	1	Hereditary sensory and autonomic neuropathy type 6 (1)
-	-	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	Benign	0.14
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	17
DANN	Benign	0.68
DEOGEN2	Benign	0.067	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.63
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.8
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.083
Sift	Benign	0.15	T
Sift4G	Benign	0.40	T
Polyphen		0.0020	B
Vest4		0.32
MVP		0.30
MPC		0.18
ClinPred		0.045	T
GERP RS		-1.3
PromoterAI		0.023	Neutral
gMVP		0.11
Mutation Taster		=91/9	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs35014998; hg19: chr6-56492845;