16-58709518-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_002080.4(GOT2):c.1069C>G(p.Gln357Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000138 in 1,613,324 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00076 ( 1 hom., cov: 33)

Exomes 𝑓: 0.000073 ( 1 hom. )

Consequence

GOT2
NM_002080.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 6.46

Variant links:

Genes affected

GOT2 (HGNC:4433): (glutamic-oxaloacetic transaminase 2) Glutamic-oxaloacetic transaminase is a pyridoxal phosphate-dependent enzyme which exists in cytoplasmic and inner-membrane mitochondrial forms, GOT1 and GOT2, respectively. GOT plays a role in amino acid metabolism and the urea and tricarboxylic acid cycles. The two enzymes are homodimeric and show close homology. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2013]

GOT2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.02688405).

BP6

Variant 16-58709518-G-C is Benign according to our data. Variant chr16-58709518-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2080831.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GOT2	NM_002080.4 linkuse as main transcript	c.1069C>G	p.Gln357Glu	missense_variant	9/10	ENST00000245206.10
GOT2	NM_001286220.2 linkuse as main transcript	c.940C>G	p.Gln314Glu	missense_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GOT2	ENST00000245206.10 linkuse as main transcript	c.1069C>G	p.Gln357Glu	missense_variant	9/10	1	NM_002080.4	P1	P00505-1
GOT2	ENST00000434819.2 linkuse as main transcript	c.940C>G	p.Gln314Glu	missense_variant	8/9	2			P00505-2
GOT2	ENST00000494627.1 linkuse as main transcript	n.420C>G		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes

AF:

0.000736

AC:

112

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00263

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000115

AC:

AN:

251418

Hom.:

AF XY:

0.0000883

AC XY:

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.00154

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000732

AC:

107

AN:

1461062

Hom.:

Cov.:

AF XY:

0.0000619

AC XY:

AN XY:

726818

show subpopulations

Gnomad4 AFR exome

AF:

0.00224

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000431

GnomAD4 genome

AF:

0.000762

AC:

116

AN:

152262

Hom.:

Cov.:

AF XY:

0.000819

AC XY:

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00272

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000138

Hom.:

Bravo

AF:

0.000737

ESP6500AA

AF:

0.00205

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000148

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 26, 2022	This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 357 of the GOT2 protein (p.Gln357Glu). This variant is present in population databases (rs112943773, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with GOT2-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GOT2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	- -

GOT2-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 25, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.067

BayesDel_noAF

Uncertain

0.13

Cadd

Uncertain

Dann

Benign

0.61

DEOGEN2

Benign

0.30

T;.

Eigen

Benign

0.10

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Benign

0.038

MetaRNN

Benign

0.027

T;T

MetaSVM

Uncertain

0.56

MutationAssessor

Benign

1.4

L;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.1

N;N

REVEL

Uncertain

0.57

Sift

Benign

0.71

T;T

Sift4G

Benign

0.93

T;T

Polyphen

0.0020

B;.

Vest4

0.34

MVP

0.88

MPC

0.42

ClinPred

0.046

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.54

gMVP

0.81

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over