rs139350480

chr6-56634196-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001374736.1(DST):c.3557G>A(p.Ser1186Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000985 in 1,613,668 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (8 hom.)
• Consequence: DST NM_001374736.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 7.91

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.

• PP2: Missense variant where missense usually causes diseases, DST
• BP4: Computational evidence support a benign effect (MetaRNN=0.0101264715).
• BP6: Variant 6-56634196-C-T is Benign according to our data. Variant chr6-56634196-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 474512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-56634196-C-T is described in Lovd as [Benign]. Variant chr6-56634196-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00525 (800/152288) while in subpopulation AFR AF= 0.0182 (756/41546). AF 95% confidence interval is 0.0171. There are 5 homozygotes in gnomad4. There are 377 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DST	NM_001374736.1	c.3557G>A	p.Ser1186Asn	missense_variant	27/104	ENST00000680361.1
DST	NM_001723.7	c.1946G>A	p.Ser649Asn	missense_variant	13/24	ENST00000370765.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DST	ENST00000680361.1	c.3557G>A	p.Ser1186Asn	missense_variant	27/104		NM_001374736.1
DST	ENST00000370765.11	c.1946G>A	p.Ser649Asn	missense_variant	13/24	1	NM_001723.7

Frequencies

GnomAD3 genomes AF: 0.00527 AC: 802 AN: 152170 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0183

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00138 AC: 347 AN: 251086 Hom.: 3 AF XY: 0.00108 AC XY: 147 AN XY: 135744

Gnomad AFR exome AF: 0.0186

Gnomad AMR exome AF: 0.000954

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000540 AC: 789 AN: 1461380 Hom.: 8 Cov.: 32 AF XY: 0.000442 AC XY: 321 AN XY: 727016

Gnomad4 AFR exome AF: 0.0186

Gnomad4 AMR exome AF: 0.00103

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000369

Gnomad4 OTH exome AF: 0.00124

GnomAD4 genome AF: 0.00525 AC: 800 AN: 152288 Hom.: 5 Cov.: 32 AF XY: 0.00506 AC XY: 377 AN XY: 74486

Gnomad4 AFR AF: 0.0182

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000871 Hom.: 7

Bravo AF: 0.00634

ESP6500AA AF: 0.0184 AC: 81

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00158 AC: 192

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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	clinical testing	GeneDx	Oct 01, 2021	See Variant Classification Assertion Criteria. -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

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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

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.11
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D;D
MetaRNN	Benign	0.010	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.45	D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.6	D;D;.;D;D;D;D;D;D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0030	D;D;.;D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;D;.;D;D
Vest4		0.68
MVP		0.83
MPC		0.55
ClinPred		0.035	T
GERP RS		5.0
gMVP		0.71

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: rs139350480; hg19: chr6-56498994; COSMIC: COSV99056304; COSMIC: COSV99056304;