20-49013912-C-T

Position:

• chr20-49013912-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006420.3(ARFGEF2):​c.4131C>T​(p.Ile1377Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.151 in 1,613,834 control chromosomes in the GnomAD database, including 21,936 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1945 hom., cov: 32)
  • Exomes 𝑓: 0.15 (19991 hom.)
• Consequence: ARFGEF2 NM_006420.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.512

Genes affected

ARFGEF2 (HGNC:15853): (ADP ribosylation factor guanine nucleotide exchange factor 2) ADP-ribosylation factors (ARFs) play an important role in intracellular vesicular trafficking. The protein encoded by this gene is involved in the activation of ARFs by accelerating replacement of bound GDP with GTP and is involved in Golgi transport. It contains a Sec7 domain, which may be responsible for its guanine-nucleotide exchange activity and also brefeldin A inhibition. [provided by RefSeq, Jul 2008]

ARFGEF2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 20-49013912-C-T is Benign according to our data. Variant chr20-49013912-C-T is described in ClinVar as [Benign]. Clinvar id is 128438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-49013912-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.512 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.35 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARFGEF2	NM_006420.3	c.4131C>T	p.Ile1377Ile	synonymous_variant	30/39	ENST00000371917.5	NP_006411.2
ARFGEF2	NM_001410846.1	c.4128C>T	p.Ile1376Ile	synonymous_variant	30/39		NP_001397775.1
ARFGEF2	XM_047439832.1	c.3567C>T	p.Ile1189Ile	synonymous_variant	28/37		XP_047295788.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARFGEF2	ENST00000371917.5	c.4131C>T	p.Ile1377Ile	synonymous_variant	30/39	1	NM_006420.3	ENSP00000360985.4

Frequencies

GnomAD3 genomes AF: 0.139 AC: 21127 AN: 151944 Hom.: 1940 Cov.: 32

Gnomad AFR AF: 0.0616

Gnomad AMI AF: 0.102

Gnomad AMR AF: 0.261

Gnomad ASJ AF: 0.0671

Gnomad EAS AF: 0.364

Gnomad SAS AF: 0.254

Gnomad FIN AF: 0.151

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.136

Gnomad OTH AF: 0.149

GnomAD3 exomes AF: 0.198 AC: 49776 AN: 251428 Hom.: 6548 AF XY: 0.192 AC XY: 26158 AN XY: 135892

Gnomad AFR exome AF: 0.0640

Gnomad AMR exome AF: 0.376

Gnomad ASJ exome AF: 0.0756

Gnomad EAS exome AF: 0.383

Gnomad SAS exome AF: 0.256

Gnomad FIN exome AF: 0.148

Gnomad NFE exome AF: 0.140

Gnomad OTH exome AF: 0.163

GnomAD4 exome AF: 0.152 AC: 222608 AN: 1461772 Hom.: 19991 Cov.: 34 AF XY: 0.155 AC XY: 112612 AN XY: 727196

Gnomad4 AFR exome AF: 0.0556

Gnomad4 AMR exome AF: 0.360

Gnomad4 ASJ exome AF: 0.0750

Gnomad4 EAS exome AF: 0.340

Gnomad4 SAS exome AF: 0.247

Gnomad4 FIN exome AF: 0.150

Gnomad4 NFE exome AF: 0.135

Gnomad4 OTH exome AF: 0.152

GnomAD4 genome AF: 0.139 AC: 21151 AN: 152062 Hom.: 1945 Cov.: 32 AF XY: 0.147 AC XY: 10894 AN XY: 74274

Gnomad4 AFR AF: 0.0619

Gnomad4 AMR AF: 0.262

Gnomad4 ASJ AF: 0.0671

Gnomad4 EAS AF: 0.363

Gnomad4 SAS AF: 0.252

Gnomad4 FIN AF: 0.151

Gnomad4 NFE AF: 0.136

Gnomad4 OTH AF: 0.150

Alfa AF: 0.137 Hom.: 1918

Bravo AF: 0.146

Asia WGS AF: 0.270 AC: 940 AN: 3478

EpiCase AF: 0.132

EpiControl AF: 0.139

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Periventricular heterotopia with microcephaly, autosomal recessive Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	5.2
DANN	Benign	0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs2281582; hg19: chr20-47630449; COSMIC: COSV64211317;