rs149172723

Positions:

• chr20-48953759-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_006420.3(ARFGEF2):​c.807C>T​(p.Asp269Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00406 in 1,614,020 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (21 hom.)
• Consequence: ARFGEF2 NM_006420.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: -6.87

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 20-48953759-C-T is Benign according to our data. Variant chr20-48953759-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 128445.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2, Benign=4}. Variant chr20-48953759-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-6.87 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00232 (353/152208) while in subpopulation NFE AF= 0.00371 (252/68010). AF 95% confidence interval is 0.00333. There are 0 homozygotes in gnomad4. There are 148 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARFGEF2	NM_006420.3	c.807C>T	p.Asp269Asp	synonymous_variant	6/39	ENST00000371917.5	NP_006411.2
ARFGEF2	NM_001410846.1	c.807C>T	p.Asp269Asp	synonymous_variant	6/39		NP_001397775.1
ARFGEF2	XM_047439832.1	c.243C>T	p.Asp81Asp	synonymous_variant	4/37		XP_047295788.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARFGEF2	ENST00000371917.5	c.807C>T	p.Asp269Asp	synonymous_variant	6/39	1	NM_006420.3	ENSP00000360985.4

Frequencies

GnomAD3 genomes AF: 0.00232 AC: 353 AN: 152090 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000990

Gnomad AMI AF: 0.0220

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00270

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00370

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00222 AC: 557 AN: 251076 Hom.: 1 AF XY: 0.00229 AC XY: 311 AN XY: 135756

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00248

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.00341

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00424 AC: 6205 AN: 1461812 Hom.: 21 Cov.: 31 AF XY: 0.00419 AC XY: 3048 AN XY: 727204

Gnomad4 AFR exome AF: 0.000627

Gnomad4 AMR exome AF: 0.00141

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00278

Gnomad4 FIN exome AF: 0.000468

Gnomad4 NFE exome AF: 0.00497

Gnomad4 OTH exome AF: 0.00533

GnomAD4 genome AF: 0.00232 AC: 353 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.00199 AC XY: 148 AN XY: 74410

Gnomad4 AFR AF: 0.000987

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00371

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00277 Hom.: 0

Bravo AF: 0.00254

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00354

EpiControl AF: 0.00368

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	ARFGEF2: BP4, BP7 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 22, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 06, 2018	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 25, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 20, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Periventricular heterotopia with microcephaly, autosomal recessive Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.089
DANN	Benign	0.54
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs149172723; hg19: chr20-47570296;