rs6909714

Variant names:

• chr6-56620688-G-A
• rs6909714
• NM_001723.7:c.3346C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-56620688-G-A
• chr6-56620688-G-T

Variant summary

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

The NM_001723.7(DST):​c.3346C>T​(p.His1116Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00373 in 1,613,836 control chromosomes in the GnomAD database, including 194 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1116R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.019 (94 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (100 hom.)
• Consequence: DST NM_001723.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.13
• Publications: 5 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: Orphanet, Ambry Genetics, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.001804322).
• BP6: Variant 6-56620688-G-A is Benign according to our data. Variant chr6-56620688-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 357588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0654 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001723.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DST	NM_001723.7	MANE Plus Clinical	c.3346C>T	p.His1116Tyr	missense	Exon 23 of 24	NP_001714.1
	DST	NM_001374736.1	MANE Select	c.4929+3842C>T		intron	N/A	NP_001361665.1
	DST	NM_001374734.1		c.4956+3842C>T		intron	N/A	NP_001361663.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DST	ENST00000370765.11	TSL:1 MANE Plus Clinical	c.3346C>T	p.His1116Tyr	missense	Exon 23 of 24	ENSP00000359801.6
	DST	ENST00000680361.1	MANE Select	c.4929+3842C>T		intron	N/A	ENSP00000505098.1
	DST	ENST00000244364.10	TSL:1	c.3318+3842C>T		intron	N/A	ENSP00000244364.6

Frequencies

GnomAD3 genomes AF: 0.0195 AC: 2961 AN: 152118 Hom.: 94 Cov.: 32

Gnomad AFR AF: 0.0676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00754

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.00546 AC: 1368 AN: 250324 AF XY: 0.00383

Gnomad AFR exome AF: 0.0691

Gnomad AMR exome AF: 0.00582

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000213

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00210 AC: 3063 AN: 1461600 Hom.: 100 Cov.: 34 AF XY: 0.00178 AC XY: 1293 AN XY: 727128

African (AFR) AF: 0.0706 AC: 2362 AN: 33458

American (AMR) AF: 0.00568 AC: 254 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53326

Middle Eastern (MID) AF: 0.00277 AC: 16 AN: 5768

European-Non Finnish (NFE) AF: 0.0000854 AC: 95 AN: 1111852

Other (OTH) AF: 0.00523 AC: 316 AN: 60390

GnomAD4 genome AF: 0.0195 AC: 2964 AN: 152236 Hom.: 94 Cov.: 32 AF XY: 0.0186 AC XY: 1382 AN XY: 74422

African (AFR) AF: 0.0675 AC: 2804 AN: 41538

American (AMR) AF: 0.00753 AC: 115 AN: 15278

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

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

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68024

Other (OTH) AF: 0.0123 AC: 26 AN: 2112

Alfa AF: 0.00727 Hom.: 82

Bravo AF: 0.0229

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0665 AC: 293

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00666 AC: 808

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000178

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	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	0.087
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	21
DANN	Uncertain	0.98
Eigen	Benign	0.055
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.1	T
PhyloP100		2.1
PROVEAN	Pathogenic	-5.0	D
REVEL	Benign	0.13
Sift	Benign	1.0	T
Sift4G	Uncertain	0.020	D
Polyphen		0.26	B
Vest4		0.29
MVP		0.30
ClinPred		0.027	T
GERP RS		4.4
Mutation Taster		=83/17	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: rs6909714; hg19: chr6-56485486;