6-56619745-G-A

Position:

• chr6-56619745-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001723.7(DST):​c.4289C>T​(p.Ala1430Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00193 in 1,614,056 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (27 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (22 hom.)
• Consequence: DST NM_001723.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.515

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024791658).
• BP6: Variant 6-56619745-G-A is Benign according to our data. Variant chr6-56619745-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 357576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0101 (1540/152236) while in subpopulation AFR AF= 0.0345 (1434/41556). AF 95% confidence interval is 0.033. There are 27 homozygotes in gnomad4. There are 740 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 27 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DST	NM_001723.7	c.4289C>T	p.Ala1430Val	missense_variant	23/24	ENST00000370765.11	NP_001714.1
DST	NM_001374736.1	c.4929+4785C>T		intron_variant		ENST00000680361.1	NP_001361665.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DST	ENST00000370765.11	c.4289C>T	p.Ala1430Val	missense_variant	23/24	1	NM_001723.7	ENSP00000359801.6
DST	ENST00000680361.1	c.4929+4785C>T		intron_variant			NM_001374736.1	ENSP00000505098.1

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1539 AN: 152118 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.0346

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00537

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00254 AC: 639 AN: 251328 Hom.: 9 AF XY: 0.00159 AC XY: 216 AN XY: 135832

Gnomad AFR exome AF: 0.0333

Gnomad AMR exome AF: 0.00199

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00108 AC: 1574 AN: 1461820 Hom.: 22 Cov.: 36 AF XY: 0.000927 AC XY: 674 AN XY: 727208

Gnomad4 AFR exome AF: 0.0344

Gnomad4 AMR exome AF: 0.00235

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000127

Gnomad4 OTH exome AF: 0.00238

GnomAD4 genome AF: 0.0101 AC: 1540 AN: 152236 Hom.: 27 Cov.: 32 AF XY: 0.00994 AC XY: 740 AN XY: 74434

Gnomad4 AFR AF: 0.0345

Gnomad4 AMR AF: 0.00537

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00804

Alfa AF: 0.00144 Hom.: 6

Bravo AF: 0.0114

ESP6500AA AF: 0.0370 AC: 163

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00311 AC: 377

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 29, 2021	- -

Hereditary sensory and autonomic neuropathy type 6;C3809470:Epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Hereditary sensory and autonomic neuropathy type 6 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.4
DANN	Benign	0.57
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.085	N
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-0.93	T
PROVEAN	Benign	0.54	N
REVEL	Benign	0.030
Sift	Benign	0.32	T
Sift4G	Benign	0.35	T
Polyphen		0.0010	B
Vest4		0.14
MVP		0.11
ClinPred		0.0011	T
GERP RS		-3.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs78701610; hg19: chr6-56484543;