20-48994597-C-A

Variant names:

• chr20-48994597-C-A
• NM_006420.3:c.3120C>A
• ARFGEF2 p.Leu1040Leu

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_006420.3(ARFGEF2):​c.3120C>A​(p.Leu1040Leu) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L1040L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARFGEF2 NM_006420.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.00005142
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.14
• Publications: 0 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: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• periventricular nodular heterotopia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP7: Synonymous conserved (PhyloP=-2.14 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006420.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARFGEF2	NM_006420.3	MANE Select	c.3120C>A	p.Leu1040Leu	splice_region synonymous	Exon 22 of 39	NP_006411.2	Q9Y6D5
	ARFGEF2	NM_001410846.1		c.3117C>A	p.Leu1039Leu	splice_region synonymous	Exon 22 of 39	NP_001397775.1	A0A7P0T7Z2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARFGEF2	ENST00000371917.5	TSL:1 MANE Select	c.3120C>A	p.Leu1040Leu	splice_region synonymous	Exon 22 of 39	ENSP00000360985.4	Q9Y6D5
	ARFGEF2	ENST00000679436.1		c.3117C>A	p.Leu1039Leu	splice_region synonymous	Exon 22 of 39	ENSP00000504888.1	A0A7P0T7Z2
	ARFGEF2	ENST00000939861.1		c.3114C>A	p.Leu1038Leu	splice_region synonymous	Exon 22 of 39	ENSP00000609920.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.16
DANN	Benign	0.56
PhyloP100		-2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000051
dbscSNV1_RF	Benign	0.11
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr20-47611134;