chr20-48995838-G-A

Position:

chr20-48995838-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_006420.3(ARFGEF2):c.3177G>A(p.Ser1059=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0104 in 1,614,148 control chromosomes in the GnomAD database, including 98 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 0.0076 ( 10 hom., cov: 32)

Exomes 𝑓: 0.011 ( 88 hom. )

Consequence

ARFGEF2
NM_006420.3 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: -6.09

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BP6

Variant 20-48995838-G-A is Benign according to our data. Variant chr20-48995838-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 128436.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=1}. Variant chr20-48995838-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-6.09 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00758 (1155/152290) while in subpopulation NFE AF= 0.0114 (776/68024). AF 95% confidence interval is 0.0107. There are 10 homozygotes in gnomad4. There are 562 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ARFGEF2	NM_006420.3 linkuse as main transcript	c.3177G>A	p.Ser1059=	synonymous_variant	23/39	ENST00000371917.5	NP_006411.2
ARFGEF2	NM_001410846.1 linkuse as main transcript	c.3174G>A	p.Ser1058=	synonymous_variant	23/39		NP_001397775.1
ARFGEF2	XM_047439832.1 linkuse as main transcript	c.2613G>A	p.Ser871=	synonymous_variant	21/37		XP_047295788.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARFGEF2	ENST00000371917.5 linkuse as main transcript	c.3177G>A	p.Ser1059=	synonymous_variant	23/39	1	NM_006420.3	ENSP00000360985	P4

Frequencies

GnomAD3 genomes

AF:

0.00760

AC:

1156

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00203

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00249

Gnomad ASJ

AF:

0.0153

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00497

Gnomad FIN

AF:

0.0160

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0114

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00784

AC:

1972

AN:

251492

Hom.:

AF XY:

0.00812

AC XY:

1103

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.00263

Gnomad ASJ exome

AF:

0.0133

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00428

Gnomad FIN exome

AF:

0.0145

Gnomad NFE exome

AF:

0.0108

Gnomad OTH exome

AF:

0.00912

GnomAD4 exome

AF:

0.0107

AC:

15599

AN:

1461858

Hom.:

Cov.:

AF XY:

0.0105

AC XY:

7643

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00137

Gnomad4 AMR exome

AF:

0.00275

Gnomad4 ASJ exome

AF:

0.0122

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00427

Gnomad4 FIN exome

AF:

0.0154

Gnomad4 NFE exome

AF:

0.0120

Gnomad4 OTH exome

AF:

0.00843

GnomAD4 genome

AF:

0.00758

AC:

1155

AN:

152290

Hom.:

Cov.:

AF XY:

0.00755

AC XY:

562

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00202

Gnomad4 AMR

AF:

0.00248

Gnomad4 ASJ

AF:

0.0153

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00497

Gnomad4 FIN

AF:

0.0160

Gnomad4 NFE

AF:

0.0114

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00672

Hom.:

Bravo

AF:

0.00640

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 30, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 21, 2015	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	ARFGEF2: BP4, BP7, BS1, BS2 -

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

-0.74

CADD

Benign

0.87

DANN

Benign

0.61

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over