Genetic Variant NM_001374736.1:c.2503C>A (chr6-56640045-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001374736.1(DST):c.2503C>A(p.Arg835Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000658 in 152,046 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R835H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

DST
NM_001374736.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.92

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

hereditary sensory and autonomic neuropathy type 6
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
epidermolysis bullosa simplex 3, localized or generalized intermediate, with BP230 deficiency
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet

DST links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001374736.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DST	NM_001374736.1	MANE Select	c.2503C>A	p.Arg835Ser	missense	Exon 19 of 104	NP_001361665.1
DST	NM_001723.7	MANE Plus Clinical	c.892C>A	p.Arg298Ser	missense	Exon 5 of 24	NP_001714.1
DST	NM_001374734.1		c.2530C>A	p.Arg844Ser	missense	Exon 19 of 103	NP_001361663.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DST	ENST00000680361.1	MANE Select	c.2503C>A	p.Arg835Ser	missense	Exon 19 of 104	ENSP00000505098.1
DST	ENST00000370765.11	TSL:1 MANE Plus Clinical	c.892C>A	p.Arg298Ser	missense	Exon 5 of 24	ENSP00000359801.6
DST	ENST00000244364.10	TSL:1	c.892C>A	p.Arg298Ser	missense	Exon 5 of 84	ENSP00000244364.6

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152046

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152046

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74254

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41382

American (AMR)

AF:

0.00

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10580

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.030

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.084

Eigen

Benign

0.12

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.78

M_CAP

Benign

0.059

MetaRNN

Uncertain

0.53

MetaSVM

Uncertain

0.30

MutationAssessor

Uncertain

2.4

PhyloP100

3.9

PrimateAI

Benign

0.21

PROVEAN

Pathogenic

-4.5

REVEL

Uncertain

0.40

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.0020

Polyphen

0.79

Vest4

0.48

MVP

0.77

MPC

0.28

ClinPred

0.96

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

gMVP

0.46

Mutation Taster

=63/37

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over