19-38879295-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_012237.4(SIRT2):c.1030C>A(p.Leu344Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00067 in 1,613,384 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0037 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (8 hom.)
• Consequence: SIRT2 NM_012237.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.65

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

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0077384114).
• BP6: Variant 19-38879295-G-T is Benign according to our data. Variant chr19-38879295-G-T is described in ClinVar as [Benign]. Clinvar id is 712248.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIRT2	NM_012237.4	c.1030C>A	p.Leu344Ile	missense_variant	16/16	ENST00000249396.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIRT2	ENST00000249396.12	c.1030C>A	p.Leu344Ile	missense_variant	16/16	1	NM_012237.4	P4

Frequencies

GnomAD3 genomes AF: 0.00368 AC: 560 AN: 152174 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00294

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.000921 AC: 229 AN: 248638 Hom.: 4 AF XY: 0.000676 AC XY: 91 AN XY: 134620

Gnomad AFR exome AF: 0.0121

Gnomad AMR exome AF: 0.000813

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000268

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.000357 AC: 521 AN: 1461092 Hom.: 8 Cov.: 32 AF XY: 0.000279 AC XY: 203 AN XY: 726892

Gnomad4 AFR exome AF: 0.0116

Gnomad4 AMR exome AF: 0.00108

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.00113

GnomAD4 genome AF: 0.00368 AC: 560 AN: 152292 Hom.: 5 Cov.: 32 AF XY: 0.00340 AC XY: 253 AN XY: 74460

Gnomad4 AFR AF: 0.0122

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.000549 Hom.: 0

Bravo AF: 0.00443

ESP6500AA AF: 0.00953 AC: 42

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00110 AC: 134

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.28	T;.;T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.89	D
MetaRNN	Benign	0.0077	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	M;.;.
MutationTaster	Benign	0.98	D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.4	N;N;.
REVEL	Benign	0.13
Sift	Uncertain	0.022	D;T;.
Sift4G	Benign	0.069	T;.;T
Polyphen		0.40	B;P;.
Vest4		0.36
MVP		0.51
MPC		0.78
ClinPred		0.051	T
GERP RS		3.8
Varity_R		0.31
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs147134890; hg19: chr19-39369935;