rs4715630

Variant names:

• chr6-56552484-C-T
• rs4715630
• NM_001374736.1:c.16308G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-56552484-C-T
• chr6-56552484-C-A

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.16308G>A​(p.Met5436Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.758 in 1,613,688 control chromosomes in the GnomAD database, including 465,341 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M5436L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.79 (48223 hom., cov: 32)
  • Exomes 𝑓: 0.75 (417118 hom.)
• Consequence: DST NM_001374736.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.386
• Publications: 41 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=6.4669354E-7).
• BP6: Variant 6-56552484-C-T is Benign according to our data. Variant chr6-56552484-C-T is described in ClinVar as Benign. ClinVar VariationId is 518376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.899 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.16308G>A	p.Met5436Ile	missense	Exon 61 of 104	NP_001361665.1	A0A7P0T890
	DST	NM_001374734.1		c.16335G>A	p.Met5445Ile	missense	Exon 61 of 103	NP_001361663.1
	DST	NM_001374722.1		c.16308G>A	p.Met5436Ile	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.16308G>A	p.Met5436Ile	missense	Exon 61 of 104	ENSP00000505098.1	A0A7P0T890
	DST	ENST00000244364.10	TSL:1	c.8439G>A	p.Met2813Ile	missense	Exon 42 of 84	ENSP00000244364.6	Q03001-8
	DST	ENST00000361203.7	TSL:5	c.15675G>A	p.Met5225Ile	missense	Exon 57 of 98	ENSP00000354508.3	F8W9J4

Frequencies

GnomAD3 genomes AF: 0.791 AC: 120280 AN: 152006 Hom.: 48150 Cov.: 32

Gnomad AFR AF: 0.906

Gnomad AMI AF: 0.561

Gnomad AMR AF: 0.727

Gnomad ASJ AF: 0.637

Gnomad EAS AF: 0.804

Gnomad SAS AF: 0.691

Gnomad FIN AF: 0.831

Gnomad MID AF: 0.601

Gnomad NFE AF: 0.750

Gnomad OTH AF: 0.729

GnomAD2 exomes AF: 0.758 AC: 188309 AN: 248588 AF XY: 0.751

Gnomad AFR exome AF: 0.912

Gnomad AMR exome AF: 0.752

Gnomad ASJ exome AF: 0.644

Gnomad EAS exome AF: 0.802

Gnomad FIN exome AF: 0.832

Gnomad NFE exome AF: 0.746

Gnomad OTH exome AF: 0.727

GnomAD4 exome AF: 0.754 AC: 1102138 AN: 1461564 Hom.: 417118 Cov.: 65 AF XY: 0.751 AC XY: 545810 AN XY: 727064

African (AFR) AF: 0.915 AC: 30618 AN: 33478

American (AMR) AF: 0.749 AC: 33493 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.646 AC: 16871 AN: 26134

East Asian (EAS) AF: 0.784 AC: 31131 AN: 39696

South Asian (SAS) AF: 0.690 AC: 59543 AN: 86248

European-Finnish (FIN) AF: 0.828 AC: 44192 AN: 53374

Middle Eastern (MID) AF: 0.643 AC: 3710 AN: 5768

European-Non Finnish (NFE) AF: 0.754 AC: 837740 AN: 1111790

Other (OTH) AF: 0.743 AC: 44840 AN: 60366

GnomAD4 genome AF: 0.792 AC: 120417 AN: 152124 Hom.: 48223 Cov.: 32 AF XY: 0.791 AC XY: 58810 AN XY: 74362

African (AFR) AF: 0.907 AC: 37630 AN: 41510

American (AMR) AF: 0.727 AC: 11115 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.637 AC: 2210 AN: 3470

East Asian (EAS) AF: 0.805 AC: 4158 AN: 5168

South Asian (SAS) AF: 0.691 AC: 3330 AN: 4818

European-Finnish (FIN) AF: 0.831 AC: 8790 AN: 10576

Middle Eastern (MID) AF: 0.619 AC: 182 AN: 294

European-Non Finnish (NFE) AF: 0.750 AC: 50954 AN: 67980

Other (OTH) AF: 0.731 AC: 1539 AN: 2106

Alfa AF: 0.757 Hom.: 116361

Bravo AF: 0.788

TwinsUK AF: 0.749 AC: 2776

ALSPAC AF: 0.753 AC: 2902

ESP6500AA AF: 0.908 AC: 3409

ESP6500EA AF: 0.742 AC: 6093

ExAC AF: 0.760 AC: 91756

Asia WGS AF: 0.775 AC: 2696 AN: 3478

EpiCase AF: 0.734

EpiControl AF: 0.727

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)
-	-	2	not specified (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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.59
DANN	Benign	0.86
DEOGEN2	Benign	0.0091	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.25	T
MetaRNN	Benign	6.5e-7	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.39
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.039
Sift	Benign	0.50	T
Polyphen		0.0	B
Vest4		0.13
MPC		0.13
ClinPred		0.0087	T
GERP RS		-8.7
gMVP		0.12
Mutation Taster		=99/1	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: rs4715630; hg19: chr6-56417282; COSMIC: COSV55023039; COSMIC: COSV55023039;