6-56624614-C-T

Position:

• chr6-56624614-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001374736.1(DST):​c.4845G>A​(p.Arg1615=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0129 in 1,611,390 control chromosomes in the GnomAD database, including 173 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (11 hom., cov: 32)
  • Exomes 𝑓: 0.013 (162 hom.)
• Consequence: DST NM_001374736.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.290

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 6-56624614-C-T is Benign according to our data. Variant chr6-56624614-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 474518.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-56624614-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.29 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0104 (1574/152050) while in subpopulation NFE AF= 0.016 (1088/67960). AF 95% confidence interval is 0.0152. There are 11 homozygotes in gnomad4. There are 728 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DST	NM_001374736.1	c.4845G>A	p.Arg1615=	synonymous_variant	36/104	ENST00000680361.1	NP_001361665.1
DST	NM_001723.7	c.3234G>A	p.Arg1078=	synonymous_variant	22/24	ENST00000370765.11	NP_001714.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DST	ENST00000680361.1	c.4845G>A	p.Arg1615=	synonymous_variant	36/104		NM_001374736.1	ENSP00000505098
DST	ENST00000370765.11	c.3234G>A	p.Arg1078=	synonymous_variant	22/24	1	NM_001723.7	ENSP00000359801

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1574 AN: 151932 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00266

Gnomad AMI AF: 0.0636

Gnomad AMR AF: 0.0116

Gnomad ASJ AF: 0.0251

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00208

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0160

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.0103 AC: 2583 AN: 250688 Hom.: 22 AF XY: 0.0102 AC XY: 1384 AN XY: 135468

Gnomad AFR exome AF: 0.00265

Gnomad AMR exome AF: 0.00920

Gnomad ASJ exome AF: 0.0247

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00216

Gnomad FIN exome AF: 0.00177

Gnomad NFE exome AF: 0.0158

Gnomad OTH exome AF: 0.0129

GnomAD4 exome AF: 0.0131 AC: 19146 AN: 1459340 Hom.: 162 Cov.: 30 AF XY: 0.0127 AC XY: 9235 AN XY: 726166

Gnomad4 AFR exome AF: 0.00233

Gnomad4 AMR exome AF: 0.00946

Gnomad4 ASJ exome AF: 0.0223

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00208

Gnomad4 FIN exome AF: 0.00250

Gnomad4 NFE exome AF: 0.0153

Gnomad4 OTH exome AF: 0.0128

GnomAD4 genome AF: 0.0104 AC: 1574 AN: 152050 Hom.: 11 Cov.: 32 AF XY: 0.00979 AC XY: 728 AN XY: 74344

Gnomad4 AFR AF: 0.00265

Gnomad4 AMR AF: 0.0115

Gnomad4 ASJ AF: 0.0251

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00208

Gnomad4 FIN AF: 0.00170

Gnomad4 NFE AF: 0.0160

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.0150 Hom.: 8

Bravo AF: 0.0111

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0166

EpiControl AF: 0.0178

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	Mar 08, 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

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	8.0
DANN	Benign	0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs41271870; hg19: chr6-56489412;