Genetic Variant SIRT2:p.Ala198Thr (chr19-38883666-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_012237.4(SIRT2):c.592G>A(p.Ala198Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000711 in 1,614,114 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0038 ( 5 hom., cov: 31)

Exomes 𝑓: 0.00039 ( 1 hom. )

Consequence

SIRT2
NM_012237.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.211

Publications

3 publications found

Variant links:

Genes affected

SIRT2 (HGNC:10886): (sirtuin 2) This gene encodes a member of the sirtuin family of proteins, homologs to the yeast Sir2 protein. Members of the sirtuin family are characterized by a sirtuin core domain and grouped into four classes. The functions of human sirtuins have not yet been determined; however, yeast sirtuin proteins are known to regulate epigenetic gene silencing and suppress recombination of rDNA. Studies suggest that the human sirtuins may function as intracellular regulatory proteins with mono-ADP-ribosyltransferase activity. The protein encoded by this gene is included in class I of the sirtuin family. Several transcript variants are resulted from alternative splicing of this gene. [provided by RefSeq, Jul 2010]

SIRT2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0036205053).

BP6

Variant 19-38883666-C-T is Benign according to our data. Variant chr19-38883666-C-T is described in ClinVar as Benign. ClinVar VariationId is 781449.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012237.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SIRT2	NM_012237.4	MANE Select	c.592G>A	p.Ala198Thr	missense	Exon 9 of 16	NP_036369.2
SIRT2	NM_030593.3		c.481G>A	p.Ala161Thr	missense	Exon 8 of 15	NP_085096.1	Q8IXJ6-2
SIRT2	NM_001193286.2		c.481G>A	p.Ala161Thr	missense	Exon 8 of 13	NP_001180215.1	A0A0A0MRF5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SIRT2	ENST00000249396.12	TSL:1 MANE Select	c.592G>A	p.Ala198Thr	missense	Exon 9 of 16	ENSP00000249396.7	Q8IXJ6-1
SIRT2	ENST00000392081.6	TSL:1	c.481G>A	p.Ala161Thr	missense	Exon 8 of 15	ENSP00000375931.2	Q8IXJ6-2
SIRT2	ENST00000462654.5	TSL:1	n.1363G>A		non_coding_transcript_exon	Exon 6 of 13

Frequencies

GnomAD3 genomes

AF:

0.00375

AC:

571

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0133

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.000995

AC:

250

AN:

251376

AF XY:

0.000788

show subpopulations

Gnomad AFR exome

AF:

0.0138

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000880

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000392

AC:

573

AN:

1461788

Hom.:

Cov.:

AF XY:

0.000359

AC XY:

261

AN XY:

727204

show subpopulations

African (AFR)

AF:

0.0128

AC:

430

AN:

33476

American (AMR)

AF:

0.000425

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.000126

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000603

AC:

AN:

1111940

Other (OTH)

AF:

0.000811

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

122

152

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.00377

AC:

574

AN:

152326

Hom.:

Cov.:

AF XY:

0.00346

AC XY:

258

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.0134

AC:

556

AN:

41576

American (AMR)

AF:

0.000523

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68030

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

122

153

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00161

Hom.:

Bravo

AF:

0.00432

ESP6500AA

AF:

0.0104

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00125

AC:

152

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.52

CADD

Benign

0.68

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.075

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.080

MetaRNN

Benign

0.0036

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.090

PhyloP100

-0.21

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.18

REVEL

Benign

0.12

Sift

Benign

0.68

Sift4G

Benign

0.70

Polyphen

0.0010

Vest4

0.088

MVP

0.040

MPC

0.21

ClinPred

0.0034

GERP RS

-8.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.17

gMVP

0.32

Mutation Taster

=96/4

polymorphism

(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

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