rs17249437

Variant names:

• chr14-67634170-T-C
• rs17249437
• NM_001172.4:c.185-8016T>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.185-8016T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.408 in 152,052 control chromosomes in the GnomAD database, including 15,208 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 0.41 (15208 hom., cov: 31)
• Consequence: ARG2 NM_001172.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00400
• Publications: 8 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

ENSG00000286861 (HGNC:):

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 = 0.684 is higher than 0.05.

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.185-8016T>C		intron	N/A	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.185-8016T>C		intron	N/A	ENSP00000261783.3	P78540
	ARG2	ENST00000927904.1		c.185-8016T>C		intron	N/A	ENSP00000597963.1
	ARG2	ENST00000556491.1	TSL:5	n.183-8016T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.407 AC: 61885 AN: 151934 Hom.: 15157 Cov.: 31

Gnomad AFR AF: 0.690

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.431

Gnomad ASJ AF: 0.299

Gnomad EAS AF: 0.454

Gnomad SAS AF: 0.358

Gnomad FIN AF: 0.289

Gnomad MID AF: 0.421

Gnomad NFE AF: 0.257

Gnomad OTH AF: 0.423

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

GnomAD4 genome AF: 0.408 AC: 62014 AN: 152052 Hom.: 15208 Cov.: 31 AF XY: 0.407 AC XY: 30248 AN XY: 74338

African (AFR) AF: 0.691 AC: 28624 AN: 41444

American (AMR) AF: 0.432 AC: 6599 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.299 AC: 1036 AN: 3466

East Asian (EAS) AF: 0.454 AC: 2343 AN: 5166

South Asian (SAS) AF: 0.360 AC: 1738 AN: 4828

European-Finnish (FIN) AF: 0.289 AC: 3052 AN: 10574

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

European-Non Finnish (NFE) AF: 0.257 AC: 17470 AN: 67978

Other (OTH) AF: 0.428 AC: 903 AN: 2110

Alfa AF: 0.363 Hom.: 1631

Bravo AF: 0.435

Asia WGS AF: 0.435 AC: 1514 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.5
DANN	Benign	0.63
PhyloP100		0.0040
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: rs17249437; hg19: chr14-68100887;