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GeneBe

19-38879699-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3

The NM_012237.4(SIRT2):c.880G>T(p.Asp294Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

SIRT2
NM_012237.4 missense

Scores

2
11
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.87
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1
In a mutagenesis_site Reduces binding for the peptide inhibitor S2iL5. (size 0) in uniprot entity SIR2_HUMAN
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.758

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SIRT2NM_012237.4 linkuse as main transcriptc.880G>T p.Asp294Tyr missense_variant 14/16 ENST00000249396.12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SIRT2ENST00000249396.12 linkuse as main transcriptc.880G>T p.Asp294Tyr missense_variant 14/161 NM_012237.4 P4Q8IXJ6-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1414224
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
699208
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 08, 2022The c.880G>T (p.D294Y) alteration is located in exon 14 (coding exon 14) of the SIRT2 gene. This alteration results from a G to T substitution at nucleotide position 880, causing the aspartic acid (D) at amino acid position 294 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.45
BayesDel_addAF
Uncertain
0.025
T
BayesDel_noAF
Benign
-0.20
Cadd
Pathogenic
30
Dann
Uncertain
0.99
DEOGEN2
Uncertain
0.70
D;.;T
Eigen
Uncertain
0.35
Eigen_PC
Uncertain
0.31
FATHMM_MKL
Uncertain
0.95
D
M_CAP
Benign
0.048
D
MetaRNN
Pathogenic
0.76
D;D;D
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.3
M;.;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.71
T
PROVEAN
Pathogenic
-4.5
D;D;.
REVEL
Benign
0.23
Sift
Uncertain
0.0020
D;D;.
Sift4G
Uncertain
0.0090
D;.;D
Polyphen
0.97
D;D;.
Vest4
0.79
MutPred
0.52
Loss of disorder (P = 0.0269);.;.;
MVP
0.52
MPC
0.64
ClinPred
0.96
D
GERP RS
4.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.56
gMVP
0.77

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.22
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.22
Position offset: -34

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-39370339; API