14-67626868-T-C

Variant names:

• chr14-67626868-T-C
• rs4902501
• NM_001172.4:c.184+5902T>C

Variant summary

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

The NM_001172.4(ARG2):​c.184+5902T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.398 in 152,118 control chromosomes in the GnomAD database, including 14,595 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 0.40 (14595 hom., cov: 32)
• Consequence: ARG2 NM_001172.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.03
• 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]

LOC124903331 (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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.678 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARG2	NM_001172.4	c.184+5902T>C		intron_variant	Intron 2 of 7	ENST00000261783.4	NP_001163.1
LOC124903331	XR_007064218.1	n.3594A>G		non_coding_transcript_exon_variant	Exon 2 of 2
GPHN	XM_047430879.1	c.1313-108327T>C		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.184+5902T>C		intron_variant	Intron 2 of 7	1	NM_001172.4	ENSP00000261783.3
ARG2	ENST00000556491.1	n.182+5902T>C		intron_variant	Intron 2 of 3	5
ARG2	ENST00000557120.5	n.226+5902T>C		intron_variant	Intron 2 of 4	2

Frequencies

GnomAD3 genomes AF: 0.397 AC: 60415 AN: 152000 Hom.: 14547 Cov.: 32

Gnomad AFR AF: 0.684

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.374

Gnomad ASJ AF: 0.299

Gnomad EAS AF: 0.453

Gnomad SAS AF: 0.358

Gnomad FIN AF: 0.289

Gnomad MID AF: 0.421

Gnomad NFE AF: 0.252

Gnomad OTH AF: 0.412

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

GnomAD4 genome AF: 0.398 AC: 60536 AN: 152118 Hom.: 14595 Cov.: 32 AF XY: 0.397 AC XY: 29489 AN XY: 74360

African (AFR) AF: 0.684 AC: 28384 AN: 41474

American (AMR) AF: 0.375 AC: 5727 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.299 AC: 1036 AN: 3468

East Asian (EAS) AF: 0.453 AC: 2351 AN: 5192

South Asian (SAS) AF: 0.361 AC: 1738 AN: 4820

European-Finnish (FIN) AF: 0.289 AC: 3055 AN: 10578

Middle Eastern (MID) AF: 0.422 AC: 124 AN: 294

European-Non Finnish (NFE) AF: 0.252 AC: 17115 AN: 67980

Other (OTH) AF: 0.416 AC: 880 AN: 2114

Alfa AF: 0.342 Hom.: 1426

Bravo AF: 0.420

Asia WGS AF: 0.432 AC: 1502 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.6
DANN	Benign	0.78
PhyloP100		-1.0
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: rs4902501; hg19: chr14-68093585;