rs4902503

Variant names:

• chr14-67632756-A-G
• rs4902503
• NM_001172.4:c.185-9430A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001172.4(ARG2):​c.185-9430A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.434 in 149,168 control chromosomes in the GnomAD database, including 18,167 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.43 (18167 hom., cov: 27)
• Consequence: ARG2 NM_001172.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.756
• Publications: 2 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]

ENSG00000286861 (HGNC:):

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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, ClinGen
• hereditary hyperekplexia

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

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.793 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARG2	NM_001172.4	c.185-9430A>G		intron_variant	Intron 2 of 7	ENST00000261783.4	NP_001163.1
GPHN	XM_047430879.1	c.1313-102439A>G		intron_variant	Intron 14 of 14		XP_047286835.1
LOC124903331	XR_007064218.1	n.1122-3416T>C		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARG2	ENST00000261783.4	c.185-9430A>G		intron_variant	Intron 2 of 7	1	NM_001172.4	ENSP00000261783.3
ARG2	ENST00000556491.1	n.183-9430A>G		intron_variant	Intron 2 of 3	5
ARG2	ENST00000557120.5	n.227-9430A>G		intron_variant	Intron 2 of 4	2
ENSG00000286861	ENST00000662787.1	n.1084-3416T>C		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.434 AC: 64645 AN: 149054 Hom.: 18111 Cov.: 27

Gnomad AFR AF: 0.800

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.436

Gnomad ASJ AF: 0.298

Gnomad EAS AF: 0.452

Gnomad SAS AF: 0.356

Gnomad FIN AF: 0.274

Gnomad MID AF: 0.439

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.444

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.434 AC: 64772 AN: 149168 Hom.: 18167 Cov.: 27 AF XY: 0.431 AC XY: 31263 AN XY: 72524

African (AFR) AF: 0.800 AC: 32292 AN: 40340

American (AMR) AF: 0.437 AC: 6474 AN: 14822

Ashkenazi Jewish (ASJ) AF: 0.298 AC: 1031 AN: 3460

East Asian (EAS) AF: 0.451 AC: 2291 AN: 5076

South Asian (SAS) AF: 0.358 AC: 1700 AN: 4754

European-Finnish (FIN) AF: 0.274 AC: 2676 AN: 9756

Middle Eastern (MID) AF: 0.441 AC: 128 AN: 290

European-Non Finnish (NFE) AF: 0.253 AC: 17124 AN: 67686

Other (OTH) AF: 0.449 AC: 931 AN: 2074

Alfa AF: 0.382 Hom.: 1912

Bravo AF: 0.470

Asia WGS AF: 0.443 AC: 1542 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.74
DANN	Benign	0.70
PhyloP100		-0.76
Mutation Taster		=100/0	polymorphism (auto)

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: rs4902503; hg19: chr14-68099473;