14-67650779-G-A

Position:

• chr14-67650779-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_001172.4(ARG2):​c.924G>A​(p.Ala308=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00186 in 1,614,122 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (5 hom.)
• Consequence: ARG2 NM_001172.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.11

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]

VTI1B (HGNC:17793): (vesicle transport through interaction with t-SNAREs 1B) Enables SNARE binding activity and chloride channel inhibitor activity. Involved in regulation of protein localization to plasma membrane. Located in several cellular components, including endosome membrane; lysosomal membrane; and perinuclear region of cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

GPHN (HGNC:):

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 14-67650779-G-A is Benign according to our data. Variant chr14-67650779-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 770239.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.11 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARG2	NM_001172.4	c.924G>A	p.Ala308=	synonymous_variant	8/8	ENST00000261783.4
VTI1B	NM_006370.3	c.*606C>T		3_prime_UTR_variant	6/6	ENST00000554659.6
GPHN	XM_047430879.1	c.1313-84416G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARG2	ENST00000261783.4	c.924G>A	p.Ala308=	synonymous_variant	8/8	1	NM_001172.4	P1
VTI1B	ENST00000554659.6	c.*606C>T		3_prime_UTR_variant	6/6	1	NM_006370.3	P1
ARG2	ENST00000557319.1	n.598G>A		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes AF: 0.00209 AC: 318 AN: 152134 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00511

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00201

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00172 AC: 433 AN: 251384 Hom.: 2 AF XY: 0.00177 AC XY: 240 AN XY: 135854

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00246

Gnomad ASJ exome AF: 0.00585

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000457

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00200

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00183 AC: 2678 AN: 1461870 Hom.: 5 Cov.: 31 AF XY: 0.00180 AC XY: 1311 AN XY: 727234

Gnomad4 AFR exome AF: 0.00206

Gnomad4 AMR exome AF: 0.00275

Gnomad4 ASJ exome AF: 0.00551

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000464

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.00188

Gnomad4 OTH exome AF: 0.00267

GnomAD4 genome AF: 0.00209 AC: 318 AN: 152252 Hom.: 2 Cov.: 32 AF XY: 0.00171 AC XY: 127 AN XY: 74438

Gnomad4 AFR AF: 0.00164

Gnomad4 AMR AF: 0.00510

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00201

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00234 Hom.: 0

Bravo AF: 0.00228

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00382

EpiControl AF: 0.00320

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	ARG2: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 16, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	11
DANN	Benign	0.61

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

Publications

LitVar

Other links and lift over

dbSNP: rs45584632; hg19: chr14-68117496;