2-240869268-C-T

Position:

• chr2-240869268-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000307503.4(AGXT):​c.264C>T​(p.Ala88=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.181 in 1,613,658 control chromosomes in the GnomAD database, including 29,448 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2031 hom., cov: 33)
  • Exomes 𝑓: 0.19 (27417 hom.)
• Consequence: AGXT ENST00000307503.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:7
• Conservation: PhyloP100: -2.96

Genes affected

AGXT (HGNC:341): (alanine--glyoxylate aminotransferase) This gene is expressed only in the liver and the encoded protein is localized mostly in the peroxisomes, where it is involved in glyoxylate detoxification. Mutations in this gene, some of which alter subcellular targetting, have been associated with type I primary hyperoxaluria. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-240869268-C-T is Benign according to our data. Variant chr2-240869268-C-T is described in ClinVar as [Benign]. Clinvar id is 204030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240869268-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.96 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.199 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGXT	NM_000030.3	c.264C>T	p.Ala88=	synonymous_variant	2/11	ENST00000307503.4	NP_000021.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGXT	ENST00000307503.4	c.264C>T	p.Ala88=	synonymous_variant	2/11	1	NM_000030.3	ENSP00000302620	P1
AGXT	ENST00000472436.1	n.284C>T		non_coding_transcript_exon_variant	2/5	2

Frequencies

GnomAD3 genomes AF: 0.146 AC: 22140 AN: 152118 Hom.: 2028 Cov.: 33

Gnomad AFR AF: 0.0603

Gnomad AMI AF: 0.253

Gnomad AMR AF: 0.119

Gnomad ASJ AF: 0.179

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.0735

Gnomad FIN AF: 0.237

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.202

Gnomad OTH AF: 0.159

GnomAD3 exomes AF: 0.148 AC: 37132 AN: 250912 Hom.: 3545 AF XY: 0.150 AC XY: 20355 AN XY: 135678

Gnomad AFR exome AF: 0.0613

Gnomad AMR exome AF: 0.0809

Gnomad ASJ exome AF: 0.182

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.0724

Gnomad FIN exome AF: 0.245

Gnomad NFE exome AF: 0.203

Gnomad OTH exome AF: 0.169

GnomAD4 exome AF: 0.185 AC: 270691 AN: 1461422 Hom.: 27417 Cov.: 35 AF XY: 0.182 AC XY: 132468 AN XY: 727020

Gnomad4 AFR exome AF: 0.0608

Gnomad4 AMR exome AF: 0.0836

Gnomad4 ASJ exome AF: 0.178

Gnomad4 EAS exome AF: 0.000327

Gnomad4 SAS exome AF: 0.0763

Gnomad4 FIN exome AF: 0.239

Gnomad4 NFE exome AF: 0.207

Gnomad4 OTH exome AF: 0.169

GnomAD4 genome AF: 0.145 AC: 22145 AN: 152236 Hom.: 2031 Cov.: 33 AF XY: 0.144 AC XY: 10704 AN XY: 74438

Gnomad4 AFR AF: 0.0603

Gnomad4 AMR AF: 0.119

Gnomad4 ASJ AF: 0.179

Gnomad4 EAS AF: 0.000966

Gnomad4 SAS AF: 0.0744

Gnomad4 FIN AF: 0.237

Gnomad4 NFE AF: 0.202

Gnomad4 OTH AF: 0.157

Alfa AF: 0.159 Hom.: 1112

Bravo AF: 0.135

Asia WGS AF: 0.0340 AC: 117 AN: 3478

EpiCase AF: 0.203

EpiControl AF: 0.200

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary hyperoxaluria, type I Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Uncertain significance, no assertion criteria provided	research	Clinical Biochemistry Laboratory, Health Services Laboratory	Nov 27, 2014	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 09, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.8
DANN	Benign	0.33
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs35698882; hg19: chr2-241808685; COSMIC: COSV56756090; COSMIC: COSV56756090;