rs141523606

Positions:

• chr6-56639763-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 3P and 12B. PM2 PP2 BP4_Strong BP6_Very_Strong

The NM_001374736.1(DST):​c.2630C>T​(p.Thr877Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000175 in 1,613,452 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts 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. T877A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (1 hom.)
• Consequence: DST NM_001374736.1 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.24

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 -9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, DST
• BP4: Computational evidence support a benign effect (MetaRNN=0.012625515).
• BP6: Variant 6-56639763-G-A is Benign according to our data. Variant chr6-56639763-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 474505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DST	NM_001374736.1	c.2630C>T	p.Thr877Ile	missense_variant	20/104	ENST00000680361.1
DST	NM_001723.7	c.1019C>T	p.Thr340Ile	missense_variant	6/24	ENST00000370765.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DST	ENST00000680361.1	c.2630C>T	p.Thr877Ile	missense_variant	20/104		NM_001374736.1
DST	ENST00000370765.11	c.1019C>T	p.Thr340Ile	missense_variant	6/24	1	NM_001723.7

Frequencies

GnomAD3 genomes AF: 0.000349 AC: 53 AN: 152012 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000580

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00521

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000479 AC: 120 AN: 250592 Hom.: 0 AF XY: 0.000413 AC XY: 56 AN XY: 135666

Gnomad AFR exome AF: 0.000754

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00511

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.000493

GnomAD4 exome AF: 0.000157 AC: 229 AN: 1461326 Hom.: 1 Cov.: 33 AF XY: 0.000154 AC XY: 112 AN XY: 726998

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00353

Gnomad4 SAS exome AF: 0.000313

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.000596

GnomAD4 genome AF: 0.000348 AC: 53 AN: 152126 Hom.: 0 Cov.: 32 AF XY: 0.000390 AC XY: 29 AN XY: 74362

Gnomad4 AFR AF: 0.000578

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00522

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000291 Hom.: 0

Bravo AF: 0.000382

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000412 AC: 50

Asia WGS AF: 0.00347 AC: 12 AN: 3470

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 05, 2024

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 06, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.013	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.55	D
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-4.4	D;D;.;D;D;D;D;D;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0070	D;D;.;D;D;T;D;D;D
Polyphen		0.74	P;.;.;.;.;D;.;D;B
Vest4		0.60
MVP		0.79
MPC		0.57
ClinPred		0.066	T
GERP RS		4.7
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs141523606; hg19: chr6-56504561; COSMIC: COSV55016139; COSMIC: COSV55016139;