20-48921796-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.-94C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 1,178,504 control chromosomes in the GnomAD database, including 31,952 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.16 ( 2571 hom., cov: 32)

Exomes 𝑓: 0.23 ( 29381 hom. )

Consequence

ARFGEF2
NM_006420.3 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.328

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 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:

ENSG00000294533 (HGNC:):

ENSG00000294533 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=-0.75).

BP6

Variant 20-48921796-C-T is Benign according to our data. Variant chr20-48921796-C-T is described in ClinVar as [Benign]. Clinvar id is 338676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.235 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARFGEF2	NM_006420.3 link	c.-94C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 39	ENST00000371917.5	NP_006411.2	Q9Y6D5Q86TH5Q59FR3
ARFGEF2	NM_006420.3 link	c.-94C>T		5_prime_UTR_variant	Exon 1 of 39	ENST00000371917.5	NP_006411.2	Q9Y6D5Q86TH5Q59FR3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARFGEF2	ENST00000371917.5 link	c.-94C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 39	1	NM_006420.3	ENSP00000360985.4		Q9Y6D5
ARFGEF2	ENST00000371917.5 link	c.-94C>T		5_prime_UTR_variant	Exon 1 of 39	1	NM_006420.3	ENSP00000360985.4		Q9Y6D5

Frequencies

GnomAD3 genomes

AF:

0.161

AC:

24348

AN:

151592

Hom.:

2570

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0412

Gnomad AMI

AF:

0.419

Gnomad AMR

AF:

0.145

Gnomad ASJ

AF:

0.154

Gnomad EAS

AF:

0.0503

Gnomad SAS

AF:

0.0853

Gnomad FIN

AF:

0.226

Gnomad MID

AF:

0.121

Gnomad NFE

AF:

0.238

Gnomad OTH

AF:

0.135

GnomAD4 exome

AF:

0.234

AC:

240303

AN:

1026804

Hom.:

29381

AF XY:

0.234

AC XY:

114387

AN XY:

488646

show subpopulations

African (AFR)

AF:

0.0293

AC:

581

AN:

19856

American (AMR)

AF:

0.163

AC:

964

AN:

5920

Ashkenazi Jewish (ASJ)

AF:

0.171

AC:

1864

AN:

10904

East Asian (EAS)

AF:

0.0853

AC:

1599

AN:

18736

South Asian (SAS)

AF:

0.0915

AC:

1876

AN:

20508

European-Finnish (FIN)

AF:

0.235

AC:

7059

AN:

30050

Middle Eastern (MID)

AF:

0.136

AC:

393

AN:

2882

European-Non Finnish (NFE)

AF:

0.248

AC:

218296

AN:

879318

Other (OTH)

AF:

0.199

AC:

7671

AN:

38630

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

8489

16978

25468

33957

42446

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.161

AC:

24350

AN:

151700

Hom.:

2571

Cov.:

AF XY:

0.156

AC XY:

11601

AN XY:

74172

show subpopulations

African (AFR)

AF:

0.0411

AC:

1706

AN:

41484

American (AMR)

AF:

0.145

AC:

2207

AN:

15228

Ashkenazi Jewish (ASJ)

AF:

0.154

AC:

534

AN:

3470

East Asian (EAS)

AF:

0.0502

AC:

258

AN:

5136

South Asian (SAS)

AF:

0.0860

AC:

414

AN:

4816

European-Finnish (FIN)

AF:

0.226

AC:

2367

AN:

10460

Middle Eastern (MID)

AF:

0.123

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.238

AC:

16160

AN:

67794

Other (OTH)

AF:

0.136

AC:

286

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1008

2016

3024

4032

5040

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.146

Hom.:

397

Bravo

AF:

0.149

Asia WGS

AF:

0.0880

AC:

304

AN:

3462

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 14, 2018

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. -

Periventricular heterotopia with microcephaly, autosomal recessive

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

(source)

DANN

Benign

0.90

PhyloP100

-0.33

PromoterAI

-0.016

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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20-48921796-C-T

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