SETX p.Ser2612Gly

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_015046.7(SETX):c.7834A>G(p.Ser2612Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0525 in 1,609,902 control chromosomes in the GnomAD database, including 6,176 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.087 ( 1076 hom., cov: 31)

Exomes 𝑓: 0.049 ( 5100 hom. )

Consequence

SETX
NM_015046.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: -1.45

Publications

21 publications found

Variant links:

Genes affected

SETX (HGNC:445): (senataxin) This gene encodes a protein named for its homology to the Sen1p protein of fungi which has RNA helicase activity encoded by a domain at the C-terminal end of the protein. The protein encoded by this gene contains a DNA/RNA helicase domain at its C-terminal end which suggests that it may be involved in both DNA and RNA processing. Mutations in this gene have been associated with ataxia-ocular apraxia-2 (AOA2) and an autosomal dominant form of juvenile amyotrophic lateral sclerosis (ALS4). [provided by RefSeq, Jul 2008]

SETX Gene-Disease associations (from GenCC):

amyotrophic lateral sclerosis type 4
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
distal hereditary motor neuropathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

SETX links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_015046.7, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002356708).

BP6

Variant 9-132264439-T-C is Benign according to our data. Variant chr9-132264439-T-C is described in ClinVar as Benign. ClinVar VariationId is 195975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.363 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015046.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SETX	NM_015046.7	MANE Select	c.7834A>G	p.Ser2612Gly	missense	Exon 26 of 26	NP_055861.3
SETX	NM_001351528.2		c.7921A>G	p.Ser2641Gly	missense	Exon 27 of 27	NP_001338457.1	Q7Z333-4
SETX	NM_001351527.2		c.7834A>G	p.Ser2612Gly	missense	Exon 26 of 26	NP_001338456.1	Q7Z333-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SETX	ENST00000224140.6	TSL:1 MANE Select	c.7834A>G	p.Ser2612Gly	missense	Exon 26 of 26	ENSP00000224140.5	Q7Z333-1
SETX	ENST00000923216.1		c.7960A>G	p.Ser2654Gly	missense	Exon 28 of 28	ENSP00000593275.1
SETX	ENST00000923217.1		c.7873A>G	p.Ser2625Gly	missense	Exon 27 of 27	ENSP00000593276.1

Frequencies

GnomAD3 genomes

AF:

0.0870

AC:

13180

AN:

151436

Hom.:

1070

Cov.:

show subpopulations

Gnomad AFR

AF:

0.164

Gnomad AMI

AF:

0.0308

Gnomad AMR

AF:

0.0740

Gnomad ASJ

AF:

0.0519

Gnomad EAS

AF:

0.377

Gnomad SAS

AF:

0.129

Gnomad FIN

AF:

0.0476

Gnomad MID

AF:

0.108

Gnomad NFE

AF:

0.0273

Gnomad OTH

AF:

0.0770

GnomAD2 exomes

AF:

0.0854

AC:

21453

AN:

251308

AF XY:

0.0811

show subpopulations

Gnomad AFR exome

AF:

0.166

Gnomad AMR exome

AF:

0.101

Gnomad ASJ exome

AF:

0.0483

Gnomad EAS exome

AF:

0.386

Gnomad FIN exome

AF:

0.0446

Gnomad NFE exome

AF:

0.0268

Gnomad OTH exome

AF:

0.0637

GnomAD4 exome

AF:

0.0489

AC:

71257

AN:

1458338

Hom.:

5100

Cov.:

AF XY:

0.0497

AC XY:

36087

AN XY:

725638

show subpopulations

African (AFR)

AF:

0.171

AC:

5698

AN:

33374

American (AMR)

AF:

0.0991

AC:

4425

AN:

44648

Ashkenazi Jewish (ASJ)

AF:

0.0488

AC:

1269

AN:

25982

East Asian (EAS)

AF:

0.394

AC:

15577

AN:

39564

South Asian (SAS)

AF:

0.105

AC:

9018

AN:

86236

European-Finnish (FIN)

AF:

0.0455

AC:

2398

AN:

52750

Middle Eastern (MID)

AF:

0.0826

AC:

474

AN:

5740

European-Non Finnish (NFE)

AF:

0.0253

AC:

28034

AN:

1109922

Other (OTH)

AF:

0.0726

AC:

4364

AN:

60122

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

4630

9260

13891

18521

23151

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1440

2880

4320

5760

7200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0872

AC:

13213

AN:

151564

Hom.:

1076

Cov.:

AF XY:

0.0905

AC XY:

6704

AN XY:

74092

show subpopulations

African (AFR)

AF:

0.164

AC:

6798

AN:

41350

American (AMR)

AF:

0.0747

AC:

1135

AN:

15196

Ashkenazi Jewish (ASJ)

AF:

0.0519

AC:

180

AN:

3470

East Asian (EAS)

AF:

0.377

AC:

1910

AN:

5072

South Asian (SAS)

AF:

0.129

AC:

607

AN:

4708

European-Finnish (FIN)

AF:

0.0476

AC:

503

AN:

10572

Middle Eastern (MID)

AF:

0.105

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0273

AC:

1851

AN:

67882

Other (OTH)

AF:

0.0805

AC:

170

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

543

1087

1630

2174

2717

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

288

432

576

720

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0518

Hom.:

2526

Bravo

AF:

0.0950

Asia WGS

AF:

0.253

AC:

878

AN:

3478

EpiCase

AF:

0.0308

EpiControl

AF:

0.0314

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (8)

not provided (3)

Amyotrophic lateral sclerosis type 4 (2)

Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (2)

Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2;C1865409:Amyotrophic lateral sclerosis type 4 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.57

CADD

Benign

0.52

(source)

DANN

Benign

0.70

DEOGEN2

Benign

0.093

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.55

MetaRNN

Benign

0.0024

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.93

PhyloP100

-1.4

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.33

REVEL

Benign

0.21

Sift

Benign

0.65

Sift4G

Benign

0.71

Varity_R

0.016

gMVP

0.12

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over