dbSNP rs573729300: ARFGEF2:c.-24_-1delGTCAGCCCCCGCCGGGCCGGGGCC (chr20-48921858-GCGGGGCCGTCAGCCCCCGCCGGGC-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_ModerateBS1

The NM_006420.3(ARFGEF2):c.-24_-1delGTCAGCCCCCGCCGGGCCGGGGCC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000413 in 1,503,662 control chromosomes in the GnomAD database, including 1 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00030 ( 1 hom. )

Consequence

ARFGEF2
NM_006420.3 5_prime_UTR

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 3.03

Publications

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

ARFGEF2 links:

ENSG00000294533 (HGNC:):

ENSG00000294533 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP6

Variant 20-48921858-GCGGGGCCGTCAGCCCCCGCCGGGC-G is Benign according to our data. Variant chr20-48921858-GCGGGGCCGTCAGCCCCCGCCGGGC-G is described in ClinVar as Likely_benign. ClinVar VariationId is 418016.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00144 (219/152010) while in subpopulation AFR AF = 0.00427 (177/41500). AF 95% confidence interval is 0.00375. There are 0 homozygotes in GnomAd4. There are 103 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.-24_-1delGTCAGCCCCCGCCGGGCCGGGGCC		5_prime_UTR	Exon 1 of 39	NP_006411.2	Q9Y6D5
	ARFGEF2	NM_001410846.1		c.-24_-1delGTCAGCCCCCGCCGGGCCGGGGCC		5_prime_UTR	Exon 1 of 39	NP_001397775.1	A0A7P0T7Z2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ARFGEF2	ENST00000371917.5	TSL:1 MANE Select	c.-24_-1delGTCAGCCCCCGCCGGGCCGGGGCC	5_prime_UTR	Exon 1 of 39	ENSP00000360985.4	Q9Y6D5
ARFGEF2	ENST00000939861.1		c.-24_-1delGTCAGCCCCCGCCGGGCCGGGGCC	5_prime_UTR	Exon 1 of 39	ENSP00000609920.1
ARFGEF2	ENST00000963182.1		c.-24_-1delGTCAGCCCCCGCCGGGCCGGGGCC	5_prime_UTR	Exon 1 of 37	ENSP00000633241.1

Frequencies

GnomAD3 genomes

AF:

0.00144

AC:

219

AN:

151900

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00428

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000284

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000383

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.000455

AC:

AN:

118654

AF XY:

0.000420

show subpopulations

Gnomad AFR exome

AF:

0.00776

Gnomad AMR exome

AF:

0.0000995

Gnomad ASJ exome

AF:

0.000138

Gnomad EAS exome

AF:

0.000160

Gnomad FIN exome

AF:

0.000268

Gnomad NFE exome

AF:

0.000409

Gnomad OTH exome

AF:

0.000612

GnomAD4 exome

AF:

0.000297

AC:

402

AN:

1351652

Hom.:

AF XY:

0.000321

AC XY:

214

AN XY:

666382

show subpopulations

African (AFR)

AF:

0.00485

AC:

133

AN:

27410

American (AMR)

AF:

0.000318

AC:

AN:

31452

Ashkenazi Jewish (ASJ)

AF:

0.0000427

AC:

AN:

23446

East Asian (EAS)

AF:

0.0000657

AC:

AN:

30456

South Asian (SAS)

AF:

0.0000932

AC:

AN:

75136

European-Finnish (FIN)

AF:

0.000294

AC:

AN:

47650

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5340

European-Non Finnish (NFE)

AF:

0.000202

AC:

213

AN:

1055224

Other (OTH)

AF:

0.000396

AC:

AN:

55538

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.00144

AC:

219

AN:

152010

Hom.:

Cov.:

AF XY:

0.00139

AC XY:

103

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.00427

AC:

177

AN:

41500

American (AMR)

AF:

0.000524

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000194

AC:

AN:

5144

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000284

AC:

AN:

10552

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000383

AC:

AN:

67930

Other (OTH)

AF:

0.00189

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

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:

0.00102

Hom.:

Bravo

AF:

0.00159

Asia WGS

AF:

0.000289

AC:

AN:

3470

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

ARFGEF2-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.0

Splicing

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