NM_001172.4:c.367G>T

Variant names:

• chr14-67645647-G-T
• rs755657562
• NM_001172.4:c.367G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001172.4(ARG2):​c.367G>T​(p.Ala123Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,106 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: ARG2 NM_001172.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.02

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:15465): (gephyrin) This gene encodes a neuronal assembly protein that anchors inhibitory neurotransmitter receptors to the postsynaptic cytoskeleton via high affinity binding to a receptor subunit domain and tubulin dimers. In nonneuronal tissues, the encoded protein is also required for molybdenum cofactor biosynthesis. Mutations in this gene may be associated with the neurological condition hyperplexia and also lead to molybdenum cofactor deficiency. Numerous alternatively spliced transcript variants encoding different isoforms have been described; however, the full-length nature of all transcript variants is not currently known. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARG2	NM_001172.4	c.367G>T	p.Ala123Ser	missense_variant	Exon 4 of 8	ENST00000261783.4	NP_001163.1
GPHN	XM_047430879.1	c.1313-89548G>T		intron_variant	Intron 14 of 14		XP_047286835.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARG2	ENST00000261783.4	c.367G>T	p.Ala123Ser	missense_variant	Exon 4 of 8	1	NM_001172.4	ENSP00000261783.3
ARG2	ENST00000557120.5	n.409G>T		non_coding_transcript_exon_variant	Exon 4 of 5	2
ARG2	ENST00000556491.1	n.361-997G>T		intron_variant	Intron 3 of 3	5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152106 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152106 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74304

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.056	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Benign	1.5	L
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.63
Sift	Benign	0.057	T
Sift4G	Benign	0.13	T
Polyphen		0.88	P
Vest4		0.29
MutPred		0.54		Gain of catalytic residue at S128 (P = 0);
MVP		0.65
MPC		0.67
ClinPred		0.91	D
GERP RS		4.9
Varity_R		0.67
gMVP		0.86

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: rs755657562; hg19: chr14-68112364;