6-56618125-A-G

Position:

chr6-56618125-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001723.7(DST):c.5909T>C(p.Phe1970Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00436 in 1,614,142 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0030 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0045 ( 35 hom. )

Consequence

DST
NM_001723.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 4.38

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009896845).

BP6

Variant 6-56618125-A-G is Benign according to our data. Variant chr6-56618125-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 357561.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2, Benign=2}. Variant chr6-56618125-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00303 (461/152284) while in subpopulation SAS AF= 0.012 (58/4816). AF 95% confidence interval is 0.00956. There are 1 homozygotes in gnomad4. There are 210 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 35 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DST	NM_001723.7 link	c.5909T>C	p.Phe1970Ser	missense_variant	23/24	ENST00000370765.11	NP_001714.1	Q03001-3
DST	NM_001374736.1 link	c.4930-3641T>C		intron_variant		ENST00000680361.1	NP_001361665.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DST	ENST00000370765.11 link	c.5909T>C	p.Phe1970Ser	missense_variant	23/24	1	NM_001723.7	ENSP00000359801.6		Q03001-3
DST	ENST00000680361.1 link	c.4930-3641T>C		intron_variant			NM_001374736.1	ENSP00000505098.1		A0A7P0T890

Frequencies

GnomAD3 genomes

AF:

0.00302

AC:

460

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000700

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0118

Gnomad FIN

AF:

0.00207

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00491

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00434

AC:

1091

AN:

251226

Hom.:

AF XY:

0.00471

AC XY:

640

AN XY:

135768

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.00107

Gnomad ASJ exome

AF:

0.000497

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0107

Gnomad FIN exome

AF:

0.00217

Gnomad NFE exome

AF:

0.00558

Gnomad OTH exome

AF:

0.00539

GnomAD4 exome

AF:

0.00450

AC:

6581

AN:

1461858

Hom.:

Cov.:

AF XY:

0.00473

AC XY:

3440

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.000627

Gnomad4 AMR exome

AF:

0.000984

Gnomad4 ASJ exome

AF:

0.000689

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0108

Gnomad4 FIN exome

AF:

0.00337

Gnomad4 NFE exome

AF:

0.00460

Gnomad4 OTH exome

AF:

0.00373

GnomAD4 genome

AF:

0.00303

AC:

461

AN:

152284

Hom.:

Cov.:

AF XY:

0.00282

AC XY:

210

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.000698

Gnomad4 AMR

AF:

0.000654

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0120

Gnomad4 FIN

AF:

0.00207

Gnomad4 NFE

AF:

0.00491

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00448

Hom.:

Bravo

AF:

0.00244

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00430

AC:

ExAC

AF:

0.00483

AC:

587

Asia WGS

AF:

0.00751

AC:

AN:

3478

EpiCase

AF:

0.00480

EpiControl

AF:

0.00403

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 04, 2022	See Variant Classification Assertion Criteria. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 25, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	DST: BP4, BS1, BS2 -

Hereditary sensory and autonomic neuropathy type 6

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

-0.48

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Uncertain

1.0

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.59

MetaRNN

Benign

0.0099

MetaSVM

Benign

-1.1

PROVEAN

Benign

-0.17

REVEL

Benign

0.17

Sift

Benign

0.13

Sift4G

Benign

0.41

Polyphen

0.99

Vest4

0.68

MVP

0.55

ClinPred

0.037

GERP RS

5.5

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over