rs773047712

Variant names:

• chr14-67620072-C-T
• rs773047712
• NM_001172.4:c.95C>T

Your query was ambiguous. Multiple possible variants found:

• chr14-67620072-C-T
• chr14-67620072-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001172.4(ARG2):​c.95C>T​(p.Pro32Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,456,218 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ARG2 NM_001172.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.49
• Publications: 0 publications found

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]

GPHN Gene-Disease associations (from GenCC):

• sulfite oxidase deficiency due to molybdenum cofactor deficiency type C

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• hereditary hyperekplexia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.879

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001172.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARG2	NM_001172.4	MANE Select	c.95C>T	p.Pro32Leu	missense	Exon 1 of 8	NP_001163.1	P78540

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARG2	ENST00000261783.4	TSL:1 MANE Select	c.95C>T	p.Pro32Leu	missense	Exon 1 of 8	ENSP00000261783.3	P78540
	ARG2	ENST00000927904.1		c.95C>T	p.Pro32Leu	missense	Exon 1 of 7	ENSP00000597963.1
	ARG2	ENST00000556491.1	TSL:5	n.93C>T		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000417 AC: 1 AN: 239902 AF XY: 0.00000768

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000299

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1456218 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 724142

African (AFR) AF: 0.00 AC: 0 AN: 33094

American (AMR) AF: 0.0000453 AC: 2 AN: 44170

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25940

East Asian (EAS) AF: 0.00 AC: 0 AN: 39214

South Asian (SAS) AF: 0.00 AC: 0 AN: 85344

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53126

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109408

Other (OTH) AF: 0.00 AC: 0 AN: 60168

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		1.5
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-8.8	D
REVEL	Uncertain	0.48
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.021	D
Polyphen		1.0	D
Vest4		0.56
MutPred		0.81		Gain of catalytic residue at F33 (P = 2e-04)
MVP		0.68
MPC		0.58
ClinPred		1.0	D
GERP RS		3.6
PromoterAI		-0.012	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.90
gMVP		0.88
Mutation Taster		=66/34	polymorphism

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

Other links and lift over

dbSNP: rs773047712; hg19: chr14-68086789;