20-48921830-C-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_006420.3(ARFGEF2):​c.-60C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00014 in 1,438,442 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

ARFGEF2
NM_006420.3 5_prime_UTR

Scores

2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.0540

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 -5 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.81).
BS1
Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000164 (25/151996) while in subpopulation NFE AF = 0.000236 (16/67924). AF 95% confidence interval is 0.000147. There are 0 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ARFGEF2NM_006420.3 linkc.-60C>T 5_prime_UTR_variant Exon 1 of 39 ENST00000371917.5 NP_006411.2 Q9Y6D5Q86TH5Q59FR3
ARFGEF2NM_001410846.1 linkc.-60C>T 5_prime_UTR_variant Exon 1 of 39 NP_001397775.1
ARFGEF2XM_047439832.1 linkc.-469C>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.-60C>T 5_prime_UTR_variant Exon 1 of 39 1 NM_006420.3 ENSP00000360985.4 Q9Y6D5

Frequencies

GnomAD3 genomes
AF:
0.000165
AC:
25
AN:
151890
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00144
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000950
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000236
Gnomad OTH
AF:
0.000479
GnomAD4 exome
AF:
0.000138
AC:
177
AN:
1286446
Hom.:
0
AF XY:
0.000159
AC XY:
101
AN XY:
633966
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
25092
American (AMR)
AF:
0.0000825
AC:
2
AN:
24228
Ashkenazi Jewish (ASJ)
AF:
0.00246
AC:
51
AN:
20770
East Asian (EAS)
AF:
0.00
AC:
0
AN:
26088
South Asian (SAS)
AF:
0.00
AC:
0
AN:
69946
European-Finnish (FIN)
AF:
0.0000444
AC:
2
AN:
45044
Middle Eastern (MID)
AF:
0.000633
AC:
3
AN:
4738
European-Non Finnish (NFE)
AF:
0.0000991
AC:
101
AN:
1018952
Other (OTH)
AF:
0.000349
AC:
18
AN:
51588
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.541
Heterozygous variant carriers
0
10
20
29
39
49
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
10
20
30
40
50
<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:
0.000164
AC:
25
AN:
151996
Hom.:
0
Cov.:
32
AF XY:
0.000202
AC XY:
15
AN XY:
74316
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41514
American (AMR)
AF:
0.000131
AC:
2
AN:
15270
Ashkenazi Jewish (ASJ)
AF:
0.00144
AC:
5
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5158
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4820
European-Finnish (FIN)
AF:
0.0000950
AC:
1
AN:
10526
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
292
European-Non Finnish (NFE)
AF:
0.000236
AC:
16
AN:
67924
Other (OTH)
AF:
0.000474
AC:
1
AN:
2110
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.493
Heterozygous variant carriers
0
2
4
5
7
9
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000712
Hom.:
0
Bravo
AF:
0.000144

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:1
-
Breakthrough Genomics, Breakthrough Genomics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Periventricular heterotopia with microcephaly, autosomal recessive Uncertain:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.81
CADD
Benign
11
DANN
Benign
0.81
PhyloP100
-0.054
PromoterAI
0.0060
Neutral

Splicing

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

Publications

Other links and lift over

dbSNP: rs562458873; hg19: chr20-47538367; API