20-49010310-T-C

Position:

chr20-49010310-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_006420.3(ARFGEF2):c.3663T>C(p.Gly1221Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.333 in 1,613,896 control chromosomes in the GnomAD database, including 91,984 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.37 ( 11473 hom., cov: 32)

Exomes 𝑓: 0.33 ( 80511 hom. )

Consequence

ARFGEF2
NM_006420.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.377

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:

ARFGEF2 (HGNC:):

ARFGEF2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.55).

BP6

Variant 20-49010310-T-C is Benign according to our data. Variant chr20-49010310-T-C is described in ClinVar as [Benign]. Clinvar id is 128437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-49010310-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.377 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.535 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARFGEF2	NM_006420.3 linkuse as main transcript	c.3663T>C	p.Gly1221Gly	synonymous_variant	27/39	ENST00000371917.5	NP_006411.2	Q9Y6D5Q86TH5Q59FR3
ARFGEF2	NM_001410846.1 linkuse as main transcript	c.3660T>C	p.Gly1220Gly	synonymous_variant	27/39		NP_001397775.1
ARFGEF2	XM_047439832.1 linkuse as main transcript	c.3099T>C	p.Gly1033Gly	synonymous_variant	25/37		XP_047295788.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARFGEF2	ENST00000371917.5 linkuse as main transcript	c.3663T>C	p.Gly1221Gly	synonymous_variant	27/39	1	NM_006420.3	ENSP00000360985.4		Q9Y6D5

Frequencies

GnomAD3 genomes

AF:

0.374

AC:

56810

AN:

151940

Hom.:

11455

Cov.:

show subpopulations

Gnomad AFR

AF:

0.541

Gnomad AMI

AF:

0.478

Gnomad AMR

AF:

0.276

Gnomad ASJ

AF:

0.284

Gnomad EAS

AF:

0.188

Gnomad SAS

AF:

0.282

Gnomad FIN

AF:

0.279

Gnomad MID

AF:

0.272

Gnomad NFE

AF:

0.335

Gnomad OTH

AF:

0.323

GnomAD3 exomes

AF:

0.310

AC:

77794

AN:

251350

Hom.:

12853

AF XY:

0.307

AC XY:

41702

AN XY:

135858

show subpopulations

Gnomad AFR exome

AF:

0.537

Gnomad AMR exome

AF:

0.263

Gnomad ASJ exome

AF:

0.281

Gnomad EAS exome

AF:

0.155

Gnomad SAS exome

AF:

0.286

Gnomad FIN exome

AF:

0.279

Gnomad NFE exome

AF:

0.330

Gnomad OTH exome

AF:

0.313

GnomAD4 exome

AF:

0.328

AC:

480043

AN:

1461838

Hom.:

80511

Cov.:

AF XY:

0.326

AC XY:

236900

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.536

Gnomad4 AMR exome

AF:

0.265

Gnomad4 ASJ exome

AF:

0.284

Gnomad4 EAS exome

AF:

0.203

Gnomad4 SAS exome

AF:

0.283

Gnomad4 FIN exome

AF:

0.282

Gnomad4 NFE exome

AF:

0.337

Gnomad4 OTH exome

AF:

0.322

GnomAD4 genome

AF:

0.374

AC:

56879

AN:

152058

Hom.:

11473

Cov.:

AF XY:

0.366

AC XY:

27168

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.541

Gnomad4 AMR

AF:

0.276

Gnomad4 ASJ

AF:

0.284

Gnomad4 EAS

AF:

0.188

Gnomad4 SAS

AF:

0.282

Gnomad4 FIN

AF:

0.279

Gnomad4 NFE

AF:

0.335

Gnomad4 OTH

AF:

0.327

Alfa

AF:

0.347

Hom.:

6726

Bravo

AF:

0.375

Asia WGS

AF:

0.279

AC:

969

AN:

3478

EpiCase

AF:

0.325

EpiControl

AF:

0.319

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 30, 2013	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	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Periventricular heterotopia with microcephaly, autosomal recessive

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.55

CADD

Benign

8.6

DANN

Benign

0.68

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

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