6-56640283-G-C

Variant names:

• chr6-56640283-G-C
• rs151271595
• NM_001374736.1:c.2350C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001374736.1(DST):​c.2350C>G​(p.Pro784Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00266 in 1,614,108 control chromosomes in the GnomAD database, including 21 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P784R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (21 hom.)
• Consequence: DST NM_001374736.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 0.441
• Publications: 7 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032327473).
• BP6: Variant 6-56640283-G-C is Benign according to our data. Variant chr6-56640283-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 357616.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00181 (276/152256) while in subpopulation SAS AF = 0.00975 (47/4822). AF 95% confidence interval is 0.00753. There are 0 homozygotes in GnomAd4. There are 142 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 21 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.2350C>G	p.Pro784Ala	missense	Exon 18 of 104	NP_001361665.1	A0A7P0T890
	DST	NM_001723.7	MANE Plus Clinical	c.739C>G	p.Pro247Ala	missense	Exon 4 of 24	NP_001714.1	Q03001-3
	DST	NM_001374734.1		c.2377C>G	p.Pro793Ala	missense	Exon 18 of 103	NP_001361663.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DST	ENST00000680361.1	MANE Select	c.2350C>G	p.Pro784Ala	missense	Exon 18 of 104	ENSP00000505098.1	A0A7P0T890
	DST	ENST00000370765.11	TSL:1 MANE Plus Clinical	c.739C>G	p.Pro247Ala	missense	Exon 4 of 24	ENSP00000359801.6	Q03001-3
	DST	ENST00000244364.10	TSL:1	c.739C>G	p.Pro247Ala	missense	Exon 4 of 84	ENSP00000244364.6	Q03001-8

Frequencies

GnomAD3 genomes AF: 0.00181 AC: 276 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000580

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00974

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00216

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00307 AC: 772 AN: 251424 AF XY: 0.00360

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00308

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00314

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00275 AC: 4022 AN: 1461852 Hom.: 21 Cov.: 34 AF XY: 0.00296 AC XY: 2154 AN XY: 727230

African (AFR) AF: 0.000627 AC: 21 AN: 33480

American (AMR) AF: 0.00136 AC: 61 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00295 AC: 77 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0102 AC: 877 AN: 86258

European-Finnish (FIN) AF: 0.000412 AC: 22 AN: 53420

Middle Eastern (MID) AF: 0.00954 AC: 55 AN: 5768

European-Non Finnish (NFE) AF: 0.00244 AC: 2710 AN: 1111978

Other (OTH) AF: 0.00328 AC: 198 AN: 60394

GnomAD4 genome AF: 0.00181 AC: 276 AN: 152256 Hom.: 0 Cov.: 32 AF XY: 0.00191 AC XY: 142 AN XY: 74448

African (AFR) AF: 0.000578 AC: 24 AN: 41536

American (AMR) AF: 0.00229 AC: 35 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00975 AC: 47 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00216 AC: 147 AN: 68014

Other (OTH) AF: 0.00379 AC: 8 AN: 2110

Alfa AF: 0.00228 Hom.: 0

Bravo AF: 0.00188

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00256 AC: 22

ExAC AF: 0.00330 AC: 400

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00245

EpiControl AF: 0.00385

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	1	1	Hereditary sensory and autonomic neuropathy type 6 (2)
-	-	1	DST-related disorder (1)
-	-	1	Hereditary sensory and autonomic neuropathy type 6;C3809470:Epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	11
DANN	Benign	0.75
DEOGEN2	Benign	0.010	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.44
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.033
Sift	Benign	0.052	T
Sift4G	Benign	0.43	T
Polyphen		0.023	B
Vest4		0.12
MVP		0.37
MPC		0.14
ClinPred		0.0017	T
GERP RS		1.6
gMVP		0.39
Mutation Taster		=97/3	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: rs151271595; hg19: chr6-56505081; COSMIC: COSV55037628; COSMIC: COSV55037628;