Variant 14-67650829-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001172.4(ARG2):c.974A>G(p.Gln325Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000308 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

ARG2
NM_001172.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.32

Variant links:

Genes affected

ARG2 (HGNC:664): (arginase 2) Arginase catalyzes the hydrolysis of arginine to ornithine and urea. At least two isoforms of mammalian arginase exists (types I and II) which differ in their tissue distribution, subcellular localization, immunologic crossreactivity and physiologic function. The type II isoform encoded by this gene, is located in the mitochondria and expressed in extra-hepatic tissues, especially kidney. The physiologic role of this isoform is poorly understood; it is thought to play a role in nitric oxide and polyamine metabolism. Transcript variants of the type II gene resulting from the use of alternative polyadenylation sites have been described. [provided by RefSeq, Jul 2008]

ARG2 links:

VTI1B (HGNC:17793): (vesicle transport through interaction with t-SNAREs 1B) Enables SNARE binding activity and chloride channel inhibitor activity. Involved in regulation of protein localization to plasma membrane. Located in several cellular components, including endosome membrane; lysosomal membrane; and perinuclear region of cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

VTI1B links:

GPHN (HGNC:):

GPHN links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21880525).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ARG2	NM_001172.4 linkuse as main transcript	c.974A>G	p.Gln325Arg	missense_variant	8/8	ENST00000261783.4
VTI1B	NM_006370.3 linkuse as main transcript	c.*556T>C		3_prime_UTR_variant	6/6	ENST00000554659.6
GPHN	XM_047430879.1 linkuse as main transcript	c.1313-84366A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARG2	ENST00000261783.4 linkuse as main transcript	c.974A>G	p.Gln325Arg	missense_variant	8/8	1	NM_001172.4	P1
VTI1B	ENST00000554659.6 linkuse as main transcript	c.*556T>C		3_prime_UTR_variant	6/6	1	NM_006370.3	P1	Q9UEU0-1
ARG2	ENST00000557319.1 linkuse as main transcript			downstream_gene_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251380

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135844

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000308

AC:

AN:

1461852

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000396

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 12, 2023

The c.974A>G (p.Q325R) alteration is located in exon 8 (coding exon 8) of the ARG2 gene. This alteration results from a A to G substitution at nucleotide position 974, causing the glutamine (Q) at amino acid position 325 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.053

BayesDel_noAF

Benign

-0.10

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

Eigen

Benign

-0.029

Eigen_PC

Benign

0.16

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.73

M_CAP

Benign

0.0054

MetaRNN

Benign

0.22

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.59

REVEL

Benign

0.15

Sift

Benign

0.27

Sift4G

Benign

0.43

Polyphen

0.018

Vest4

0.11

MutPred

0.35

Gain of catalytic residue at S321 (P = 0.0065);

MVP

0.84

MPC

0.19

ClinPred

0.42

GERP RS

5.1

Varity_R

0.31

gMVP

0.77

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