14-67627548-G-C

Variant names:

• chr14-67627548-G-C
• rs12587111
• NM_001172.4:c.184+6582G>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+6582G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.205 in 151,900 control chromosomes in the GnomAD database, including 3,975 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 0.21 (3975 hom., cov: 31)
• Consequence: ARG2 NM_001172.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.683
• 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]

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=-0.5).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.353 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.184+6582G>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.184+6582G>C		intron	N/A	ENSP00000261783.3	P78540
	ARG2	ENST00000927904.1		c.184+6582G>C		intron	N/A	ENSP00000597963.1
	ENSG00000286861	ENST00000662787.1		n.2876C>G		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.205 AC: 31108 AN: 151782 Hom.: 3955 Cov.: 31

Gnomad AFR AF: 0.357

Gnomad AMI AF: 0.0866

Gnomad AMR AF: 0.251

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.228

Gnomad SAS AF: 0.193

Gnomad FIN AF: 0.140

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.117

Gnomad OTH AF: 0.230

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

GnomAD4 genome AF: 0.205 AC: 31178 AN: 151900 Hom.: 3975 Cov.: 31 AF XY: 0.206 AC XY: 15315 AN XY: 74242

African (AFR) AF: 0.357 AC: 14787 AN: 41364

American (AMR) AF: 0.251 AC: 3833 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 370 AN: 3464

East Asian (EAS) AF: 0.229 AC: 1182 AN: 5166

South Asian (SAS) AF: 0.195 AC: 938 AN: 4814

European-Finnish (FIN) AF: 0.140 AC: 1473 AN: 10546

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.117 AC: 7948 AN: 67974

Other (OTH) AF: 0.230 AC: 486 AN: 2112

Alfa AF: 0.0803 Hom.: 135

Bravo AF: 0.223

Asia WGS AF: 0.217 AC: 757 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	11
DANN	Benign	0.80
PhyloP100		0.68
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: rs12587111; hg19: chr14-68094265;