20-49013912-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.512

Publications

16 publications found

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 Gene-Disease associations (from GenCC):

periventricular heterotopia with microcephaly, autosomal recessive
Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen
periventricular nodular heterotopia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ARFGEF2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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.

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 rank	MANE	Protein	UniProt
ARFGEF2	NM_006420.3 link	c.4131C>T	p.Ile1377Ile	synonymous_variant	Exon 30 of 39	ENST00000371917.5	NP_006411.2	Q9Y6D5Q86TH5Q59FR3
ARFGEF2	NM_001410846.1 link	c.4128C>T	p.Ile1376Ile	synonymous_variant	Exon 30 of 39		NP_001397775.1
ARFGEF2	XM_047439832.1 link	c.3567C>T	p.Ile1189Ile	synonymous_variant	Exon 28 of 37		XP_047295788.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARFGEF2	ENST00000371917.5 link	c.4131C>T	p.Ile1377Ile	synonymous_variant	Exon 30 of 39	1	NM_006420.3	ENSP00000360985.4		Q9Y6D5

Frequencies

GnomAD3 genomes

AF:

0.139

AC:

21127

AN:

151944

Hom.:

1940

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.198

AC:

49776

AN:

251428

AF XY:

0.192

show subpopulations

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 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.:

AF XY:

0.155

AC XY:

112612

AN XY:

727196

show subpopulations

African (AFR)

AF:

0.0556

AC:

1862

AN:

33476

American (AMR)

AF:

0.360

AC:

16105

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0750

AC:

1960

AN:

26134

East Asian (EAS)

AF:

0.340

AC:

13490

AN:

39700

South Asian (SAS)

AF:

0.247

AC:

21324

AN:

86250

European-Finnish (FIN)

AF:

0.150

AC:

8015

AN:

53400

Middle Eastern (MID)

AF:

0.114

AC:

660

AN:

5768

European-Non Finnish (NFE)

AF:

0.135

AC:

149992

AN:

1111932

Other (OTH)

AF:

0.152

AC:

9200

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

11883

23765

35648

47530

59413

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5612

11224

16836

22448

28060

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.139

AC:

21151

AN:

152062

Hom.:

1945

Cov.:

AF XY:

0.147

AC XY:

10894

AN XY:

74274

show subpopulations

African (AFR)

AF:

0.0619

AC:

2570

AN:

41516

American (AMR)

AF:

0.262

AC:

3991

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.0671

AC:

233

AN:

3470

East Asian (EAS)

AF:

0.363

AC:

1875

AN:

5160

South Asian (SAS)

AF:

0.252

AC:

1214

AN:

4808

European-Finnish (FIN)

AF:

0.151

AC:

1589

AN:

10548

Middle Eastern (MID)

AF:

0.112

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.136

AC:

9236

AN:

67988

Other (OTH)

AF:

0.150

AC:

317

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

909

1818

2728

3637

4546

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

252

504

756

1008

1260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.137

Hom.:

2364

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

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Periventricular heterotopia with microcephaly, autosomal recessive

Benign:3

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:2

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

5.2

(source)

DANN

Benign

0.65

PhyloP100

-0.51

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over