chr6-56618606-A-G

Position:

• chr6-56618606-A-G

Variant summary

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

The ENST00000370765.11(DST):​c.5428T>C​(p.Tyr1810His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,614,096 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0062 (10 hom., cov: 32)
  • Exomes 𝑓: 0.00064 (7 hom.)
• Consequence: DST ENST00000370765.11 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.38

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=0.0045960546).
• BP6: Variant 6-56618606-A-G is Benign according to our data. Variant chr6-56618606-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 474532.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-56618606-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00618 (941/152246) while in subpopulation AFR AF= 0.022 (913/41544). AF 95% confidence interval is 0.0208. There are 10 homozygotes in gnomad4. There are 451 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DST	NM_001723.7	c.5428T>C	p.Tyr1810His	missense_variant	23/24	ENST00000370765.11	NP_001714.1
DST	NM_001374736.1	c.4930-4122T>C		intron_variant		ENST00000680361.1	NP_001361665.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DST	ENST00000370765.11	c.5428T>C	p.Tyr1810His	missense_variant	23/24	1	NM_001723.7	ENSP00000359801
DST	ENST00000680361.1	c.4930-4122T>C		intron_variant			NM_001374736.1	ENSP00000505098

Frequencies

GnomAD3 genomes AF: 0.00617 AC: 938 AN: 152128 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0220

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00162 AC: 408 AN: 251348 Hom.: 3 AF XY: 0.00107 AC XY: 146 AN XY: 135850

Gnomad AFR exome AF: 0.0223

Gnomad AMR exome AF: 0.000954

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000638 AC: 933 AN: 1461850 Hom.: 7 Cov.: 36 AF XY: 0.000527 AC XY: 383 AN XY: 727226

Gnomad4 AFR exome AF: 0.0231

Gnomad4 AMR exome AF: 0.00110

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000629

Gnomad4 OTH exome AF: 0.00151

GnomAD4 genome AF: 0.00618 AC: 941 AN: 152246 Hom.: 10 Cov.: 32 AF XY: 0.00606 AC XY: 451 AN XY: 74452

Gnomad4 AFR AF: 0.0220

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00106 Hom.: 3

Bravo AF: 0.00720

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0272 AC: 120

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00214 AC: 260

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

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	May 06, 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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	19
DANN	Uncertain	1.0
Eigen	Benign	0.042
Eigen_PC	Benign	-0.00011
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-1.1	T
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.055
Sift	Benign	0.067	T
Sift4G	Benign	0.37	T
Polyphen		0.97	D
Vest4		0.22
MVP		0.37
ClinPred		0.059	T
GERP RS		5.2

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: rs79225819; hg19: chr6-56483404;