rs151221957

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_006420.3(ARFGEF2):c.4462A>T(p.Thr1488Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00068 in 1,613,660 control chromosomes in the GnomAD database, including 4 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 0.00045 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00070 ( 4 hom. )

Consequence

ARFGEF2
NM_006420.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 9.23

Publications

9 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 links:

CSE1L-DT (HGNC:51232): (CSE1L divergent transcript)

CSE1L-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.153476).

BP6

Variant 20-49017503-A-T is Benign according to our data. Variant chr20-49017503-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 128441.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000453 (69/152170) while in subpopulation NFE AF = 0.000809 (55/68010). AF 95% confidence interval is 0.000638. There are 0 homozygotes in GnomAd4. There are 21 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 4 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006420.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARFGEF2	NM_006420.3	MANE Select	c.4462A>T	p.Thr1488Ser	missense	Exon 33 of 39	NP_006411.2	Q9Y6D5
	ARFGEF2	NM_001410846.1		c.4459A>T	p.Thr1487Ser	missense	Exon 33 of 39	NP_001397775.1	A0A7P0T7Z2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARFGEF2	ENST00000371917.5	TSL:1 MANE Select	c.4462A>T	p.Thr1488Ser	missense	Exon 33 of 39	ENSP00000360985.4	Q9Y6D5
ARFGEF2	ENST00000679436.1		c.4459A>T	p.Thr1487Ser	missense	Exon 33 of 39	ENSP00000504888.1	A0A7P0T7Z2
ARFGEF2	ENST00000939861.1		c.4456A>T	p.Thr1486Ser	missense	Exon 33 of 39	ENSP00000609920.1

Frequencies

GnomAD3 genomes

AF:

0.000454

AC:

AN:

152052

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000394

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000809

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.000386

AC:

AN:

251270

AF XY:

0.000376

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000722

Gnomad OTH exome

AF:

0.000979

GnomAD4 exome

AF:

0.000703

AC:

1028

AN:

1461490

Hom.:

Cov.:

AF XY:

0.000673

AC XY:

489

AN XY:

726998

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33474

American (AMR)

AF:

0.000403

AC:

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39652

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86174

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53384

Middle Eastern (MID)

AF:

0.000694

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000859

AC:

955

AN:

1111834

Other (OTH)

AF:

0.000729

AC:

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

108

161

215

269

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

144

180

<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:

0.000453

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.0000723

AC:

AN:

41516

American (AMR)

AF:

0.000393

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10572

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000809

AC:

AN:

68010

Other (OTH)

AF:

0.00237

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000826

Hom.:

Bravo

AF:

0.000480

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.000379

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00120

EpiControl

AF:

0.000830

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Periventricular heterotopia with microcephaly, autosomal recessive (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.027

MetaRNN

Benign

0.15

MetaSVM

Benign

-0.74

MutationAssessor

Benign

1.7

PhyloP100

9.2

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.19

Sift

Benign

0.27

Sift4G

Benign

0.27

Polyphen

0.10

Vest4

0.44

MVP

0.58

MPC

0.40

ClinPred

0.083

GERP RS

5.6

Varity_R

0.14

gMVP

0.27

Mutation Taster

=94/6

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over