chr19-38879699-C-A

Variant names:

• chr19-38879699-C-A
• rs760819880
• NM_012237.4:c.880G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.87
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.758

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.880G>T	p.Asp294Tyr	missense	Exon 14 of 16	NP_036369.2
	SIRT2	NM_030593.3		c.769G>T	p.Asp257Tyr	missense	Exon 13 of 15	NP_085096.1	Q8IXJ6-2
	SIRT2	NM_001193286.2		c.685-199G>T		intron	N/A	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.880G>T	p.Asp294Tyr	missense	Exon 14 of 16	ENSP00000249396.7	Q8IXJ6-1
	SIRT2	ENST00000392081.6	TSL:1	c.769G>T	p.Asp257Tyr	missense	Exon 13 of 15	ENSP00000375931.2	Q8IXJ6-2
	SIRT2	ENST00000462654.5	TSL:1	n.1651G>T		non_coding_transcript_exon	Exon 11 of 13

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

African (AFR) AF: 0.00 AC: 0 AN: 32282

American (AMR) AF: 0.00 AC: 0 AN: 37730

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25328

East Asian (EAS) AF: 0.00 AC: 0 AN: 36992

South Asian (SAS) AF: 0.00 AC: 0 AN: 80312

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50174

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5708

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1087086

Other (OTH) AF: 0.00 AC: 0 AN: 58612

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		4.9
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Benign	0.23
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.97	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
Mutation Taster		=54/46	polymorphism

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

Other links and lift over

dbSNP: rs760819880; hg19: chr19-39370339;