20-48952689-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006420.3(ARFGEF2):c.424-16C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0598 in 1,613,286 control chromosomes in the GnomAD database, including 3,267 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.047 ( 191 hom., cov: 32)

Exomes 𝑓: 0.061 ( 3076 hom. )

Consequence

ARFGEF2
NM_006420.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -3.60

Publications

5 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 20-48952689-C-T is Benign according to our data. Variant chr20-48952689-C-T is described in ClinVar as Benign. ClinVar VariationId is 136418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0955 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
ARFGEF2	NM_006420.3 link	c.424-16C>T	intron_variant	Intron 4 of 38	ENST00000371917.5	NP_006411.2	Q9Y6D5Q86TH5Q59FR3
ARFGEF2	NM_001410846.1 link	c.424-16C>T	intron_variant	Intron 4 of 38		NP_001397775.1
ARFGEF2	XM_047439832.1 link	c.-141-16C>T	intron_variant	Intron 2 of 36		XP_047295788.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARFGEF2	ENST00000371917.5 link	c.424-16C>T		intron_variant	Intron 4 of 38	1	NM_006420.3	ENSP00000360985.4		Q9Y6D5

Frequencies

GnomAD3 genomes

AF:

0.0473

AC:

7192

AN:

152136

Hom.:

192

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0120

Gnomad AMI

AF:

0.0187

Gnomad AMR

AF:

0.0387

Gnomad ASJ

AF:

0.0951

Gnomad EAS

AF:

0.0813

Gnomad SAS

AF:

0.103

Gnomad FIN

AF:

0.0347

Gnomad MID

AF:

0.0823

Gnomad NFE

AF:

0.0637

Gnomad OTH

AF:

0.0533

GnomAD2 exomes

AF:

0.0599

AC:

15054

AN:

251388

AF XY:

0.0652

show subpopulations

Gnomad AFR exome

AF:

0.0108

Gnomad AMR exome

AF:

0.0245

Gnomad ASJ exome

AF:

0.0935

Gnomad EAS exome

AF:

0.0694

Gnomad FIN exome

AF:

0.0334

Gnomad NFE exome

AF:

0.0635

Gnomad OTH exome

AF:

0.0653

GnomAD4 exome

AF:

0.0611

AC:

89264

AN:

1461032

Hom.:

3076

Cov.:

AF XY:

0.0632

AC XY:

45971

AN XY:

726854

show subpopulations

African (AFR)

AF:

0.0104

AC:

347

AN:

33472

American (AMR)

AF:

0.0263

AC:

1177

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0910

AC:

2376

AN:

26124

East Asian (EAS)

AF:

0.0570

AC:

2263

AN:

39698

South Asian (SAS)

AF:

0.111

AC:

9559

AN:

86220

European-Finnish (FIN)

AF:

0.0358

AC:

1910

AN:

53416

Middle Eastern (MID)

AF:

0.109

AC:

626

AN:

5750

European-Non Finnish (NFE)

AF:

0.0606

AC:

67293

AN:

1111266

Other (OTH)

AF:

0.0615

AC:

3713

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

4109

8218

12327

16436

20545

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2498

4996

7494

9992

12490

<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:

0.0472

AC:

7192

AN:

152254

Hom.:

191

Cov.:

AF XY:

0.0466

AC XY:

3472

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.0120

AC:

498

AN:

41568

American (AMR)

AF:

0.0386

AC:

591

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0951

AC:

330

AN:

3470

East Asian (EAS)

AF:

0.0815

AC:

423

AN:

5188

South Asian (SAS)

AF:

0.103

AC:

496

AN:

4816

European-Finnish (FIN)

AF:

0.0347

AC:

368

AN:

10600

Middle Eastern (MID)

AF:

0.0850

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0637

AC:

4329

AN:

68006

Other (OTH)

AF:

0.0546

AC:

115

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

341

683

1024

1366

1707

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

200

300

400

500

<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:

0.0573

Hom.:

100

Bravo

AF:

0.0448

Asia WGS

AF:

0.0640

AC:

223

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Oct 30, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

-0.92

CADD

Benign

0.0080

(source)

DANN

Benign

0.46

PhyloP100

-3.6

Mutation Taster

=23/77

disease causing

(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