rs28937880

Positions:

• chr20-48953577-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_006420.3(ARFGEF2):​c.625G>A​(p.Glu209Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000723 in 1,614,074 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00096 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00070 (7 hom.)
• Consequence: ARFGEF2 NM_006420.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:5
• Conservation: PhyloP100: 6.81

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 -12 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ARFGEF2. . Gene score misZ 2.5971 (greater than the threshold 3.09). Trascript score misZ 4.3519 (greater than threshold 3.09). GenCC has associacion of gene with periventricular nodular heterotopia, periventricular heterotopia with microcephaly, autosomal recessive.
• BP4: Computational evidence support a benign effect (MetaRNN=0.008533895).
• BP6: Variant 20-48953577-G-A is Benign according to our data. Variant chr20-48953577-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 5050.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=4, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000959 (146/152196) while in subpopulation AMR AF= 0.00713 (109/15280). AF 95% confidence interval is 0.00605. There are 1 homozygotes in gnomad4. There are 74 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARFGEF2	NM_006420.3	c.625G>A	p.Glu209Lys	missense_variant	6/39	ENST00000371917.5	NP_006411.2
ARFGEF2	NM_001410846.1	c.625G>A	p.Glu209Lys	missense_variant	6/39		NP_001397775.1
ARFGEF2	XM_047439832.1	c.61G>A	p.Glu21Lys	missense_variant	4/37		XP_047295788.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARFGEF2	ENST00000371917.5	c.625G>A	p.Glu209Lys	missense_variant	6/39	1	NM_006420.3	ENSP00000360985	P4

Frequencies

GnomAD3 genomes AF: 0.000973 AC: 148 AN: 152078 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00727

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00365

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00178 AC: 447 AN: 251374 Hom.: 2 AF XY: 0.00133 AC XY: 181 AN XY: 135868

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.0110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00277

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000698 AC: 1021 AN: 1461878 Hom.: 7 Cov.: 32 AF XY: 0.000633 AC XY: 460 AN XY: 727240

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.0116

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0110

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.000662

GnomAD4 genome AF: 0.000959 AC: 146 AN: 152196 Hom.: 1 Cov.: 32 AF XY: 0.000994 AC XY: 74 AN XY: 74416

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.00713

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00366

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000161 Hom.: 0

Bravo AF: 0.00191

ExAC AF: 0.00151 AC: 183

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Periventricular heterotopia with microcephaly, autosomal recessive Uncertain:3 Benign:2

Uncertain significance, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
Benign, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	The homozygous p.Glu209Lys variant in ARFGEF has been identified in at least 1 Turkish individual with consanguineous parents and periventricular heterotopia with microcephaly (PMID: 14647276, 28333917). This variant has also been identified in >1% of Latino chromosomes and 1 homozygote by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal recessive periventricular heterotopia with microcephaly. -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 26, 2019	- -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Jan 01, 2004	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 09, 2019	This variant is associated with the following publications: (PMID: 24278701, 23755938, 14647276, 17850229, 20857375, 26765562, 27535533, 28333917) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Oct 05, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.14	T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0085	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.22
Sift	Benign	0.12	T
Sift4G	Benign	0.70	T
Polyphen		0.29	B
Vest4		0.83
MVP		0.77
MPC		0.62
ClinPred		0.033	T
GERP RS		6.1
Varity_R		0.18
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs28937880; hg19: chr20-47570114;