20-48921997-C-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_ModerateBP6_ModerateBP7

The NM_006420.3(ARFGEF2):​c.108C>T​(p.Cys36Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000701 in 1,427,036 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 Likely benign (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

ARFGEF2
NM_006420.3 synonymous

Scores

2

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.83

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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.42).
BP6
Variant 20-48921997-C-T is Benign according to our data. Variant chr20-48921997-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1946895.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
Synonymous conserved (PhyloP=2.83 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ARFGEF2NM_006420.3 linkc.108C>T p.Cys36Cys synonymous_variant Exon 1 of 39 ENST00000371917.5 NP_006411.2 Q9Y6D5Q86TH5Q59FR3
ARFGEF2NM_001410846.1 linkc.108C>T p.Cys36Cys synonymous_variant Exon 1 of 39 NP_001397775.1
ARFGEF2XM_047439832.1 linkc.-302C>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
ARFGEF2ENST00000371917.5 linkc.108C>T p.Cys36Cys synonymous_variant Exon 1 of 39 1 NM_006420.3 ENSP00000360985.4 Q9Y6D5

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
7.01e-7
AC:
1
AN:
1427036
Hom.:
0
Cov.:
31
AF XY:
0.00000141
AC XY:
1
AN XY:
706820
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
32738
American (AMR)
AF:
0.00
AC:
0
AN:
39606
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25394
East Asian (EAS)
AF:
0.00
AC:
0
AN:
37820
South Asian (SAS)
AF:
0.00
AC:
0
AN:
81418
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
50266
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5708
European-Non Finnish (NFE)
AF:
9.13e-7
AC:
1
AN:
1095072
Other (OTH)
AF:
0.00
AC:
0
AN:
59014
⚠️ 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: 0.225
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Benign:1
May 27, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.42
CADD
Benign
18
DANN
Benign
0.95
PhyloP100
2.8
PromoterAI
0.013
Neutral
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.9

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.13
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

hg19: chr20-47538534; API