chr20-48921796-C-T

Position:

• chr20-48921796-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.328

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
ARFGEF2	NM_006420.3	c.-94C>T		5_prime_UTR_premature_start_codon_gain_variant	1/39	ENST00000371917.5	NP_006411.2
ARFGEF2	NM_006420.3	c.-94C>T		5_prime_UTR_variant	1/39	ENST00000371917.5	NP_006411.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARFGEF2	ENST00000371917	c.-94C>T		5_prime_UTR_premature_start_codon_gain_variant	1/39	1	NM_006420.3	ENSP00000360985.4
ARFGEF2	ENST00000371917	c.-94C>T		5_prime_UTR_variant	1/39	1	NM_006420.3	ENSP00000360985.4
ARFGEF2	ENST00000681399.1	n.-94C>T		upstream_gene_variant				ENSP00000506363.1

Frequencies

GnomAD3 genomes AF: 0.161 AC: 24348 AN: 151592 Hom.: 2570 Cov.: 32

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

Gnomad4 AFR exome AF: 0.0293

Gnomad4 AMR exome AF: 0.163

Gnomad4 ASJ exome AF: 0.171

Gnomad4 EAS exome AF: 0.0853

Gnomad4 SAS exome AF: 0.0915

Gnomad4 FIN exome AF: 0.235

Gnomad4 NFE exome AF: 0.248

Gnomad4 OTH exome AF: 0.199

GnomAD4 genome AF: 0.161 AC: 24350 AN: 151700 Hom.: 2571 Cov.: 32 AF XY: 0.156 AC XY: 11601 AN XY: 74172

Gnomad4 AFR AF: 0.0411

Gnomad4 AMR AF: 0.145

Gnomad4 ASJ AF: 0.154

Gnomad4 EAS AF: 0.0502

Gnomad4 SAS AF: 0.0860

Gnomad4 FIN AF: 0.226

Gnomad4 NFE AF: 0.238

Gnomad4 OTH AF: 0.136

Alfa AF: 0.150 Hom.: 396

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

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	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. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Periventricular heterotopia with microcephaly, autosomal recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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	13
DANN	Benign	0.90

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2273101; hg19: chr20-47538333;