rs41296217

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 2P and 17B. PM2BP4_StrongBP6_Very_StrongBP7BS1

The ENST00000371917.5(ARFGEF2):​c.2940C>T​(p.Thr980=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000512 in 1,614,194 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00053 ( 1 hom. )

Consequence

ARFGEF2
ENST00000371917.5 synonymous

Scores

2

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -4.22
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.82).
BP6
Variant 20-48991165-C-T is Benign according to our data. Variant chr20-48991165-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 434283.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-4.22 with no splicing effect.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000328 (50/152308) while in subpopulation NFE AF= 0.000603 (41/68036). AF 95% confidence interval is 0.000457. There are 0 homozygotes in gnomad4. There are 18 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ARFGEF2NM_006420.3 linkuse as main transcriptc.2940C>T p.Thr980= synonymous_variant 21/39 ENST00000371917.5 NP_006411.2
ARFGEF2NM_001410846.1 linkuse as main transcriptc.2937C>T p.Thr979= synonymous_variant 21/39 NP_001397775.1
ARFGEF2XM_047439832.1 linkuse as main transcriptc.2376C>T p.Thr792= synonymous_variant 19/37 XP_047295788.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ARFGEF2ENST00000371917.5 linkuse as main transcriptc.2940C>T p.Thr980= synonymous_variant 21/391 NM_006420.3 ENSP00000360985 P4

Frequencies

GnomAD3 genomes
AF:
0.000335
AC:
51
AN:
152190
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000965
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.000603
Gnomad OTH
AF:
0.000955
GnomAD3 exomes
AF:
0.000274
AC:
69
AN:
251452
Hom.:
0
AF XY:
0.000287
AC XY:
39
AN XY:
135900
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.000318
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.000484
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000531
AC:
776
AN:
1461886
Hom.:
1
Cov.:
32
AF XY:
0.000520
AC XY:
378
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.000402
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.0000374
Gnomad4 NFE exome
AF:
0.000653
Gnomad4 OTH exome
AF:
0.000430
GnomAD4 genome
AF:
0.000328
AC:
50
AN:
152308
Hom.:
0
Cov.:
32
AF XY:
0.000242
AC XY:
18
AN XY:
74476
show subpopulations
Gnomad4 AFR
AF:
0.0000963
Gnomad4 AMR
AF:
0.000196
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000603
Gnomad4 OTH
AF:
0.000945
Alfa
AF:
0.000392
Hom.:
0
Bravo
AF:
0.000382
EpiCase
AF:
0.000763
EpiControl
AF:
0.000652

ClinVar

Significance: Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Likely benign, criteria provided, single submitterclinical testingGeneDxJan 30, 2021- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJul 01, 2022ARFGEF2: BP4, BP7 -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 02, 2024- -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoApr 24, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.82
CADD
Benign
0.67
DANN
Benign
0.28
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs41296217; hg19: chr20-47607702; COSMIC: COSV64210668; API