rs376690099

Variant names:

• chr20-48921851-C-T
• rs376690099
• NM_006420.3:c.-39C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_006420.3(ARFGEF2):​c.-39C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000247 in 1,498,202 control chromosomes in the GnomAD database, including 2 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 0.00055 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (2 hom.)
• Consequence: ARFGEF2 NM_006420.3 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.66
• 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: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• periventricular nodular heterotopia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000294533 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 20-48921851-C-T is Benign according to our data. Variant chr20-48921851-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 896552.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000552 (84/152048) while in subpopulation EAS AF = 0.00912 (47/5154). AF 95% confidence interval is 0.00705. There are 0 homozygotes in GnomAd4. There are 40 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,AD gene

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.-39C>T		5_prime_UTR	Exon 1 of 39	NP_006411.2	Q9Y6D5
	ARFGEF2	NM_001410846.1		c.-39C>T		5_prime_UTR	Exon 1 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.-39C>T		5_prime_UTR	Exon 1 of 39	ENSP00000360985.4	Q9Y6D5
	ARFGEF2	ENST00000939861.1		c.-39C>T		5_prime_UTR	Exon 1 of 39	ENSP00000609920.1
	ARFGEF2	ENST00000963182.1		c.-39C>T		5_prime_UTR	Exon 1 of 37	ENSP00000633241.1

Frequencies

GnomAD3 genomes AF: 0.000546 AC: 83 AN: 151940 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00890

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000692 AC: 81 AN: 117016 AF XY: 0.000771

Gnomad AFR exome AF: 0.000313

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00910

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000212 AC: 286 AN: 1346154 Hom.: 2 Cov.: 31 AF XY: 0.000234 AC XY: 155 AN XY: 663732

African (AFR) AF: 0.000111 AC: 3 AN: 27140

American (AMR) AF: 0.0000323 AC: 1 AN: 30994

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23174

East Asian (EAS) AF: 0.00283 AC: 85 AN: 30044

South Asian (SAS) AF: 0.00156 AC: 117 AN: 75038

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5250

European-Non Finnish (NFE) AF: 0.00000665 AC: 7 AN: 1051942

Other (OTH) AF: 0.00132 AC: 73 AN: 55156

GnomAD4 genome AF: 0.000552 AC: 84 AN: 152048 Hom.: 0 Cov.: 32 AF XY: 0.000538 AC XY: 40 AN XY: 74340

African (AFR) AF: 0.000482 AC: 20 AN: 41526

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00912 AC: 47 AN: 5154

South Asian (SAS) AF: 0.00270 AC: 13 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10546

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67946

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000347 Hom.: 0

Bravo AF: 0.000450

Asia WGS AF: 0.0180 AC: 61 AN: 3470

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	1	-	Periventricular heterotopia with microcephaly, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	17
DANN	Benign	0.89
PhyloP100		1.7
PromoterAI		-0.042	Neutral

Splicing

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

Other links and lift over

dbSNP: rs376690099; hg19: chr20-47538388;