14-67645675-G-A

Position:

• chr14-67645675-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001172.4(ARG2):​c.395G>A​(p.Arg132Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000327 in 1,613,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00084 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: ARG2 NM_001172.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.40

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]

GPHN (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.012249708).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARG2	NM_001172.4	c.395G>A	p.Arg132Gln	missense_variant	4/8	ENST00000261783.4
GPHN	XM_047430879.1	c.1313-89520G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARG2	ENST00000261783.4	c.395G>A	p.Arg132Gln	missense_variant	4/8	1	NM_001172.4	P1
ARG2	ENST00000557120.5	n.437G>A		non_coding_transcript_exon_variant	4/5	2
ARG2	ENST00000556491.1	n.361-969G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.000842 AC: 128 AN: 152072 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000335 AC: 84 AN: 250978 Hom.: 0 AF XY: 0.000273 AC XY: 37 AN XY: 135616

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000490

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000282

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000274 AC: 400 AN: 1461628 Hom.: 0 Cov.: 30 AF XY: 0.000256 AC XY: 186 AN XY: 727120

Gnomad4 AFR exome AF: 0.00123

Gnomad4 AMR exome AF: 0.000492

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000403

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000243

Gnomad4 OTH exome AF: 0.000712

GnomAD4 genome AF: 0.000841 AC: 128 AN: 152190 Hom.: 0 Cov.: 32 AF XY: 0.000793 AC XY: 59 AN XY: 74418

Gnomad4 AFR AF: 0.00108

Gnomad4 AMR AF: 0.00360

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000362 Hom.: 0

Bravo AF: 0.00141

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000338 AC: 41

EpiCase AF: 0.000327

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 17, 2021

The c.395G>A (p.R132Q) alteration is located in exon 4 (coding exon 4) of the ARG2 gene. This alteration results from a G to A substitution at nucleotide position 395, causing the arginine (R) at amino acid position 132 to be replaced by a glutamine (Q). 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	0.082
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.59	N
MutationTaster	Benign	0.93	D
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.061
Sift	Benign	0.27	T
Sift4G	Benign	0.68	T
Polyphen		0.056	B
Vest4		0.13
MVP		0.34
MPC		0.21
ClinPred		0.018	T
GERP RS		1.2
Varity_R		0.11
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs151039935; hg19: chr14-68112392;