rs377322572

Variant names:

• chr20-48976194-C-T
• rs377322572
• NM_006420.3:c.1953C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS1

The NM_006420.3(ARFGEF2):​c.1953C>T​(p.Ile651Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000967 in 1,613,904 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 0.00013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000093 (0 hom.)
• Consequence: ARFGEF2 NM_006420.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.546
• Publications: 1 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: G2P, Labcorp Genetics (formerly Invitae), ClinGen
• periventricular nodular heterotopia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 20-48976194-C-T is Benign according to our data. Variant chr20-48976194-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 434278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.546 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000131 (20/152252) while in subpopulation SAS AF = 0.000829 (4/4828). AF 95% confidence interval is 0.000283. There are 1 homozygotes in GnomAd4. There are 7 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.1953C>T	p.Ile651Ile	synonymous	Exon 14 of 39	NP_006411.2	Q9Y6D5
	ARFGEF2	NM_001410846.1		c.1950C>T	p.Ile650Ile	synonymous	Exon 14 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.1953C>T	p.Ile651Ile	synonymous	Exon 14 of 39	ENSP00000360985.4	Q9Y6D5
	ARFGEF2	ENST00000679436.1		c.1950C>T	p.Ile650Ile	synonymous	Exon 14 of 39	ENSP00000504888.1	A0A7P0T7Z2
	ARFGEF2	ENST00000939861.1		c.1947C>T	p.Ile649Ile	synonymous	Exon 14 of 39	ENSP00000609920.1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152134 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000155 AC: 39 AN: 250994 AF XY: 0.000184

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000930 AC: 136 AN: 1461652 Hom.: 0 Cov.: 31 AF XY: 0.000114 AC XY: 83 AN XY: 727104

African (AFR) AF: 0.000209 AC: 7 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.000504 AC: 20 AN: 39698

South Asian (SAS) AF: 0.000812 AC: 70 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5688

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1111966

Other (OTH) AF: 0.000513 AC: 31 AN: 60374

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152252 Hom.: 1 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74450

African (AFR) AF: 0.000144 AC: 6 AN: 41534

American (AMR) AF: 0.000262 AC: 4 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5184

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.0000986 Hom.: 0

Bravo AF: 0.000128

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	ARFGEF2-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	4.0
DANN	Benign	0.79
PhyloP100		-0.55
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.9
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs377322572; hg19: chr20-47592731; COSMIC: COSV64216625;