6-56552747-T-C

Variant names:

• chr6-56552747-T-C
• rs4715631
• NM_001374736.1:c.16045A>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.16045A>G​(p.Thr5349Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.704 in 1,610,246 control chromosomes in the GnomAD database, including 400,421 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T5349T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.69 (36032 hom., cov: 32)
  • Exomes 𝑓: 0.71 (364389 hom.)
• Consequence: DST NM_001374736.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.74
• Publications: 44 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=7.1254226E-7).
• BP6: Variant 6-56552747-T-C is Benign according to our data. Variant chr6-56552747-T-C is described in ClinVar as Benign. ClinVar VariationId is 518377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.705 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.16045A>G	p.Thr5349Ala	missense	Exon 61 of 104	NP_001361665.1	A0A7P0T890
	DST	NM_001374734.1		c.16072A>G	p.Thr5358Ala	missense	Exon 61 of 103	NP_001361663.1
	DST	NM_001374722.1		c.16045A>G	p.Thr5349Ala	missense	Exon 61 of 103	NP_001361651.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DST	ENST00000680361.1	MANE Select	c.16045A>G	p.Thr5349Ala	missense	Exon 61 of 104	ENSP00000505098.1	A0A7P0T890
	DST	ENST00000244364.10	TSL:1	c.8176A>G	p.Thr2726Ala	missense	Exon 42 of 84	ENSP00000244364.6	Q03001-8
	DST	ENST00000361203.7	TSL:5	c.15412A>G	p.Thr5138Ala	missense	Exon 57 of 98	ENSP00000354508.3	F8W9J4

Frequencies

GnomAD3 genomes AF: 0.686 AC: 104162 AN: 151906 Hom.: 35990 Cov.: 32

Gnomad AFR AF: 0.630

Gnomad AMI AF: 0.566

Gnomad AMR AF: 0.687

Gnomad ASJ AF: 0.589

Gnomad EAS AF: 0.663

Gnomad SAS AF: 0.656

Gnomad FIN AF: 0.821

Gnomad MID AF: 0.576

Gnomad NFE AF: 0.710

Gnomad OTH AF: 0.648

GnomAD2 exomes AF: 0.702 AC: 172988 AN: 246430 AF XY: 0.701

Gnomad AFR exome AF: 0.631

Gnomad AMR exome AF: 0.726

Gnomad ASJ exome AF: 0.594

Gnomad EAS exome AF: 0.653

Gnomad FIN exome AF: 0.818

Gnomad NFE exome AF: 0.712

Gnomad OTH exome AF: 0.685

GnomAD4 exome AF: 0.706 AC: 1029058 AN: 1458222 Hom.: 364389 Cov.: 58 AF XY: 0.704 AC XY: 511078 AN XY: 725554

African (AFR) AF: 0.627 AC: 20997 AN: 33476

American (AMR) AF: 0.722 AC: 32298 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.599 AC: 15665 AN: 26134

East Asian (EAS) AF: 0.671 AC: 26646 AN: 39692

South Asian (SAS) AF: 0.663 AC: 57149 AN: 86254

European-Finnish (FIN) AF: 0.813 AC: 40736 AN: 50092

Middle Eastern (MID) AF: 0.622 AC: 3586 AN: 5768

European-Non Finnish (NFE) AF: 0.711 AC: 790876 AN: 1111750

Other (OTH) AF: 0.681 AC: 41105 AN: 60342

GnomAD4 genome AF: 0.686 AC: 104259 AN: 152024 Hom.: 36032 Cov.: 32 AF XY: 0.689 AC XY: 51219 AN XY: 74320

African (AFR) AF: 0.630 AC: 26082 AN: 41420

American (AMR) AF: 0.687 AC: 10496 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.589 AC: 2043 AN: 3466

East Asian (EAS) AF: 0.665 AC: 3437 AN: 5172

South Asian (SAS) AF: 0.657 AC: 3167 AN: 4824

European-Finnish (FIN) AF: 0.821 AC: 8699 AN: 10594

Middle Eastern (MID) AF: 0.592 AC: 174 AN: 294

European-Non Finnish (NFE) AF: 0.710 AC: 48278 AN: 67972

Other (OTH) AF: 0.651 AC: 1370 AN: 2104

Alfa AF: 0.697 Hom.: 131492

Bravo AF: 0.670

TwinsUK AF: 0.707 AC: 2622

ALSPAC AF: 0.707 AC: 2724

ESP6500AA AF: 0.642 AC: 2419

ESP6500EA AF: 0.702 AC: 5792

ExAC AF: 0.703 AC: 84931

Asia WGS AF: 0.663 AC: 2308 AN: 3478

EpiCase AF: 0.698

EpiControl AF: 0.694

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	15
DANN	Benign	0.82
DEOGEN2	Benign	0.0026	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.80	T
MetaRNN	Benign	7.1e-7	T
MetaSVM	Benign	-0.97	T
PhyloP100		2.7
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.97	N
REVEL	Benign	0.074
Sift	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.052
MPC		0.12
ClinPred		0.0079	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.085
Mutation Taster		=98/2	polymorphism (auto)

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: rs4715631; hg19: chr6-56417545; COSMIC: COSV55032654; COSMIC: COSV55032654;