dbSNP rs61748373: ARFGEF2:p.Ser1059Ser (chr20-48995838-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_006420.3(ARFGEF2):c.3177G>A(p.Ser1059Ser) 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). Synonymous variant affecting the same amino acid position (i.e. S1059S) has been classified as Likely benign.

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:6

Conservation

PhyloP100: -6.09

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: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen
periventricular nodular heterotopia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ARFGEF2 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_006420.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 128436.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 10 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.3177G>A	p.Ser1059Ser	synonymous	Exon 23 of 39	NP_006411.2	Q9Y6D5
	ARFGEF2	NM_001410846.1		c.3174G>A	p.Ser1058Ser	synonymous	Exon 23 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.3177G>A	p.Ser1059Ser	synonymous	Exon 23 of 39	ENSP00000360985.4	Q9Y6D5
ARFGEF2	ENST00000679436.1		c.3174G>A	p.Ser1058Ser	synonymous	Exon 23 of 39	ENSP00000504888.1	A0A7P0T7Z2
ARFGEF2	ENST00000939861.1		c.3171G>A	p.Ser1057Ser	synonymous	Exon 23 of 39	ENSP00000609920.1

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

GnomAD2 exomes

AF:

0.00784

AC:

1972

AN:

251492

AF XY:

0.00812

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 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

African (AFR)

AF:

0.00137

AC:

AN:

33480

American (AMR)

AF:

0.00275

AC:

123

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0122

AC:

319

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39696

South Asian (SAS)

AF:

0.00427

AC:

368

AN:

86256

European-Finnish (FIN)

AF:

0.0154

AC:

822

AN:

53420

Middle Eastern (MID)

AF:

0.00277

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0120

AC:

13395

AN:

1111988

Other (OTH)

AF:

0.00843

AC:

509

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

872

1744

2616

3488

4360

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

502

1004

1506

2008

2510

<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:

0.00758

AC:

1155

AN:

152290

Hom.:

Cov.:

AF XY:

0.00755

AC XY:

562

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.00202

AC:

AN:

41566

American (AMR)

AF:

0.00248

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0153

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00497

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0160

AC:

170

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0114

AC:

776

AN:

68024

Other (OTH)

AF:

0.00473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

124

187

249

311

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0101

Hom.:

Bravo

AF:

0.00640

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

not provided (2)

Periventricular heterotopia with microcephaly, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

0.87

(source)

DANN

Benign

0.61

PhyloP100

-6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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