chr14-67646576-G-A

Variant names:

• chr14-67646576-G-A
• rs742869
• NM_001172.4:c.523-68G>A

Variant summary

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

The NM_001172.4(ARG2):​c.523-68G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.546 in 1,278,946 control chromosomes in the GnomAD database, including 202,436 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 0.45 (17871 hom., cov: 32)
  • Exomes 𝑓: 0.56 (184565 hom.)
• Consequence: ARG2 NM_001172.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0580
• Publications: 19 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: 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=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.604 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARG2	NM_001172.4	MANE Select	c.523-68G>A		intron	N/A	NP_001163.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARG2	ENST00000261783.4	TSL:1 MANE Select	c.523-68G>A		intron	N/A	ENSP00000261783.3
	ARG2	ENST00000557319.1	TSL:2	n.129G>A		non_coding_transcript_exon	Exon 1 of 4
	ARG2	ENST00000556491.1	TSL:5	n.361-68G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.449 AC: 68165 AN: 151952 Hom.: 17875 Cov.: 32

Gnomad AFR AF: 0.190

Gnomad AMI AF: 0.705

Gnomad AMR AF: 0.400

Gnomad ASJ AF: 0.558

Gnomad EAS AF: 0.302

Gnomad SAS AF: 0.363

Gnomad FIN AF: 0.560

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.609

Gnomad OTH AF: 0.426

GnomAD4 exome AF: 0.560 AC: 630619 AN: 1126876 Hom.: 184565 Cov.: 15 AF XY: 0.556 AC XY: 317790 AN XY: 571476

African (AFR) AF: 0.173 AC: 4593 AN: 26584

American (AMR) AF: 0.378 AC: 15722 AN: 41600

Ashkenazi Jewish (ASJ) AF: 0.547 AC: 12069 AN: 22082

East Asian (EAS) AF: 0.279 AC: 10583 AN: 37966

South Asian (SAS) AF: 0.385 AC: 28490 AN: 73908

European-Finnish (FIN) AF: 0.553 AC: 28503 AN: 51574

Middle Eastern (MID) AF: 0.366 AC: 1852 AN: 5058

European-Non Finnish (NFE) AF: 0.615 AC: 503359 AN: 819056

Other (OTH) AF: 0.519 AC: 25448 AN: 49048

GnomAD4 genome AF: 0.448 AC: 68171 AN: 152070 Hom.: 17871 Cov.: 32 AF XY: 0.444 AC XY: 32988 AN XY: 74338

African (AFR) AF: 0.190 AC: 7891 AN: 41504

American (AMR) AF: 0.400 AC: 6101 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.558 AC: 1933 AN: 3464

East Asian (EAS) AF: 0.302 AC: 1562 AN: 5168

South Asian (SAS) AF: 0.363 AC: 1754 AN: 4826

European-Finnish (FIN) AF: 0.560 AC: 5915 AN: 10570

Middle Eastern (MID) AF: 0.374 AC: 110 AN: 294

European-Non Finnish (NFE) AF: 0.609 AC: 41374 AN: 67956

Other (OTH) AF: 0.421 AC: 888 AN: 2110

Alfa AF: 0.548 Hom.: 39528

Bravo AF: 0.423

Asia WGS AF: 0.310 AC: 1078 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.8
DANN	Benign	0.58
PhyloP100		0.058
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: rs742869; hg19: chr14-68113293; COSMIC: COSV53619850; COSMIC: COSV53619850;