chr20-49017279-A-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_006420.3(ARFGEF2):c.4346A>C(p.Asn1449Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000217 in 1,613,940 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00029 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

ARFGEF2
NM_006420.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 9.32

Publications

1 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.044669002).

BP6

Variant 20-49017279-A-C is Benign according to our data. Variant chr20-49017279-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 798173.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000289 (44/152196) while in subpopulation NFE AF = 0.000118 (8/68034). AF 95% confidence interval is 0.0000584. There are 0 homozygotes in GnomAd4. There are 25 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.4346A>C	p.Asn1449Thr	missense	Exon 32 of 39	NP_006411.2	Q9Y6D5
	ARFGEF2	NM_001410846.1		c.4343A>C	p.Asn1448Thr	missense	Exon 32 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.4346A>C	p.Asn1449Thr	missense	Exon 32 of 39	ENSP00000360985.4	Q9Y6D5
ARFGEF2	ENST00000679436.1		c.4343A>C	p.Asn1448Thr	missense	Exon 32 of 39	ENSP00000504888.1	A0A7P0T7Z2
ARFGEF2	ENST00000939861.1		c.4340A>C	p.Asn1447Thr	missense	Exon 32 of 39	ENSP00000609920.1

Frequencies

GnomAD3 genomes

AF:

0.000289

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00893

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000418

AC:

105

AN:

251316

AF XY:

0.000361

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00833

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000792

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000210

AC:

307

AN:

1461744

Hom.:

Cov.:

AF XY:

0.000190

AC XY:

138

AN XY:

727162

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00762

AC:

199

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53376

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000450

AC:

AN:

1111950

Other (OTH)

AF:

0.000662

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000289

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41470

American (AMR)

AF:

0.0000655

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00893

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68034

Other (OTH)

AF:

0.00143

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

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:

0.000647

Hom.:

Bravo

AF:

0.000291

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.000288

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

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 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.97

M_CAP

Benign

0.062

MetaRNN

Benign

0.045

MetaSVM

Uncertain

-0.23

MutationAssessor

Uncertain

2.5

PhyloP100

9.3

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-5.3

REVEL

Uncertain

0.46

Sift

Uncertain

0.0030

Sift4G

Benign

0.086

Polyphen

1.0

Vest4

0.83

MVP

0.60

MPC

1.1

ClinPred

0.17

GERP RS

5.5

Varity_R

0.74

gMVP

0.41

Mutation Taster

=33/67

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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