Genetic Variant NM_006420.3:c.48G>T (chr20-48921937-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_006420.3(ARFGEF2):c.48G>T(p.Glu16Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000000708 in 1,411,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E16E) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

ARFGEF2
NM_006420.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.70

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: 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.36211354).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARFGEF2	NM_006420.3 link	c.48G>T	p.Glu16Asp	missense_variant	Exon 1 of 39	ENST00000371917.5	NP_006411.2	Q9Y6D5Q86TH5Q59FR3
ARFGEF2	NM_001410846.1 link	c.48G>T	p.Glu16Asp	missense_variant	Exon 1 of 39		NP_001397775.1
ARFGEF2	XM_047439832.1 link	c.-362G>T		5_prime_UTR_variant	Exon 1 of 37		XP_047295788.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARFGEF2	ENST00000371917.5 link	c.48G>T	p.Glu16Asp	missense_variant	Exon 1 of 39	1	NM_006420.3	ENSP00000360985.4		Q9Y6D5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.08e-7

AC:

AN:

1411470

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

697556

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000311

AC:

AN:

32178

American (AMR)

AF:

0.00

AC:

AN:

36886

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25256

East Asian (EAS)

AF:

0.00

AC:

AN:

36740

South Asian (SAS)

AF:

0.00

AC:

AN:

80076

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49880

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5702

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1086266

Other (OTH)

AF:

0.00

AC:

AN:

58486

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.39

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.47

Eigen

Benign

0.012

Eigen_PC

Benign

0.15

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.043

MetaRNN

Benign

0.36

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.0

PhyloP100

4.7

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.042

Sift

Benign

0.11

Sift4G

Benign

0.14

Polyphen

0.024

Vest4

0.63

MutPred

0.36

Loss of methylation at K17 (P = 0.0923);

MVP

0.54

MPC

0.40

ClinPred

0.89

GERP RS

4.6

PromoterAI

-0.038

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.9

Varity_R

0.46

gMVP

0.39

Mutation Taster

=82/18

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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NM_006420.3:c.48G>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over