NM_012237.4:c.592G>C

Variant names:

• chr19-38883666-C-G
• rs34321258
• NM_012237.4:c.592G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_012237.4(SIRT2):​c.592G>C​(p.Ala198Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 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. A198T) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SIRT2 NM_012237.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.211
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.053894192).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIRT2	NM_012237.4	MANE Select	c.592G>C	p.Ala198Pro	missense	Exon 9 of 16	NP_036369.2
	SIRT2	NM_030593.3		c.481G>C	p.Ala161Pro	missense	Exon 8 of 15	NP_085096.1	Q8IXJ6-2
	SIRT2	NM_001193286.2		c.481G>C	p.Ala161Pro	missense	Exon 8 of 13	NP_001180215.1	A0A0A0MRF5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIRT2	ENST00000249396.12	TSL:1 MANE Select	c.592G>C	p.Ala198Pro	missense	Exon 9 of 16	ENSP00000249396.7	Q8IXJ6-1
	SIRT2	ENST00000392081.6	TSL:1	c.481G>C	p.Ala161Pro	missense	Exon 8 of 15	ENSP00000375931.2	Q8IXJ6-2
	SIRT2	ENST00000462654.5	TSL:1	n.1363G>C		non_coding_transcript_exon	Exon 6 of 13

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461788 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727204

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111940

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	0.40
DANN	Benign	0.47
DEOGEN2	Benign	0.065	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.050	N
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.2	N
PhyloP100		-0.21
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.16	N
REVEL	Benign	0.16
Sift	Benign	0.75	T
Sift4G	Benign	0.74	T
Polyphen		0.0	B
Vest4		0.20
MutPred		0.60		Gain of disorder (P = 0.0531)
MVP		0.085
MPC		0.28
ClinPred		0.020	T
GERP RS		-8.7
Varity_R		0.27
gMVP		0.57
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs34321258; hg19: chr19-39374306;