20-49010310-T-C

Variant names:

• chr20-49010310-T-C
• rs2295580
• NM_006420.3:c.3663T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006420.3(ARFGEF2):​c.3663T>C​(p.Gly1221Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.333 in 1,613,896 control chromosomes in the GnomAD database, including 91,984 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (11473 hom., cov: 32)
  • Exomes 𝑓: 0.33 (80511 hom.)
• Consequence: ARFGEF2 NM_006420.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.377
• Publications: 24 publications found

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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 20-49010310-T-C is Benign according to our data. Variant chr20-49010310-T-C is described in ClinVar as [Benign]. Clinvar id is 128437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.377 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.535 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARFGEF2	NM_006420.3	c.3663T>C	p.Gly1221Gly	synonymous_variant	Exon 27 of 39	ENST00000371917.5	NP_006411.2
ARFGEF2	NM_001410846.1	c.3660T>C	p.Gly1220Gly	synonymous_variant	Exon 27 of 39		NP_001397775.1
ARFGEF2	XM_047439832.1	c.3099T>C	p.Gly1033Gly	synonymous_variant	Exon 25 of 37		XP_047295788.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARFGEF2	ENST00000371917.5	c.3663T>C	p.Gly1221Gly	synonymous_variant	Exon 27 of 39	1	NM_006420.3	ENSP00000360985.4

Frequencies

GnomAD3 genomes AF: 0.374 AC: 56810 AN: 151940 Hom.: 11455 Cov.: 32

Gnomad AFR AF: 0.541

Gnomad AMI AF: 0.478

Gnomad AMR AF: 0.276

Gnomad ASJ AF: 0.284

Gnomad EAS AF: 0.188

Gnomad SAS AF: 0.282

Gnomad FIN AF: 0.279

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.335

Gnomad OTH AF: 0.323

GnomAD2 exomes AF: 0.310 AC: 77794 AN: 251350 AF XY: 0.307

Gnomad AFR exome AF: 0.537

Gnomad AMR exome AF: 0.263

Gnomad ASJ exome AF: 0.281

Gnomad EAS exome AF: 0.155

Gnomad FIN exome AF: 0.279

Gnomad NFE exome AF: 0.330

Gnomad OTH exome AF: 0.313

GnomAD4 exome AF: 0.328 AC: 480043 AN: 1461838 Hom.: 80511 Cov.: 50 AF XY: 0.326 AC XY: 236900 AN XY: 727218

African (AFR) AF: 0.536 AC: 17948 AN: 33478

American (AMR) AF: 0.265 AC: 11842 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.284 AC: 7411 AN: 26136

East Asian (EAS) AF: 0.203 AC: 8060 AN: 39698

South Asian (SAS) AF: 0.283 AC: 24378 AN: 86258

European-Finnish (FIN) AF: 0.282 AC: 15045 AN: 53388

Middle Eastern (MID) AF: 0.286 AC: 1647 AN: 5768

European-Non Finnish (NFE) AF: 0.337 AC: 374289 AN: 1111994

Other (OTH) AF: 0.322 AC: 19423 AN: 60396

GnomAD4 genome AF: 0.374 AC: 56879 AN: 152058 Hom.: 11473 Cov.: 32 AF XY: 0.366 AC XY: 27168 AN XY: 74308

African (AFR) AF: 0.541 AC: 22414 AN: 41456

American (AMR) AF: 0.276 AC: 4213 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.284 AC: 984 AN: 3466

East Asian (EAS) AF: 0.188 AC: 975 AN: 5182

South Asian (SAS) AF: 0.282 AC: 1360 AN: 4822

European-Finnish (FIN) AF: 0.279 AC: 2946 AN: 10556

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.335 AC: 22778 AN: 67988

Other (OTH) AF: 0.327 AC: 689 AN: 2106

Alfa AF: 0.347 Hom.: 7484

Bravo AF: 0.375

Asia WGS AF: 0.279 AC: 969 AN: 3478

EpiCase AF: 0.325

EpiControl AF: 0.319

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Oct 30, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

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PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Periventricular heterotopia with microcephaly, autosomal recessive Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

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 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	-0.55
CADD	Benign	8.6
DANN	Benign	0.68
PhyloP100		-0.38
Mutation Taster		=68/32	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2295580; hg19: chr20-47626847; COSMIC: COSV64212347;