20-48921863-G-A

Variant names:

• chr20-48921863-G-A
• rs550163684
• NM_006420.3:c.-27G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006420.3(ARFGEF2):​c.-27G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000634 in 1,508,868 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00065 (5 hom.)
• Consequence: ARFGEF2 NM_006420.3 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.75
• 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: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen
• periventricular nodular heterotopia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000294533 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 20-48921863-G-A is Benign according to our data. Variant chr20-48921863-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 377496.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000514 (78/151622) while in subpopulation SAS AF = 0.00642 (31/4830). AF 95% confidence interval is 0.00465. There are 0 homozygotes in GnomAd4. There are 32 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARFGEF2	NM_006420.3	c.-27G>A		5_prime_UTR_variant	Exon 1 of 39	ENST00000371917.5	NP_006411.2
ARFGEF2	NM_001410846.1	c.-27G>A		5_prime_UTR_variant	Exon 1 of 39		NP_001397775.1
ARFGEF2	XM_047439832.1	c.-436G>A		5_prime_UTR_variant	Exon 1 of 37		XP_047295788.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARFGEF2	ENST00000371917.5	c.-27G>A		5_prime_UTR_variant	Exon 1 of 39	1	NM_006420.3	ENSP00000360985.4

Frequencies

GnomAD3 genomes AF: 0.000515 AC: 78 AN: 151512 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00641

Gnomad FIN AF: 0.000284

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000442

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.00155 AC: 188 AN: 121670 AF XY: 0.00186

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00230

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000466

Gnomad NFE exome AF: 0.000419

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.000648 AC: 879 AN: 1357246 Hom.: 5 Cov.: 31 AF XY: 0.000804 AC XY: 538 AN XY: 669174

African (AFR) AF: 0.00 AC: 0 AN: 27448

American (AMR) AF: 0.00 AC: 0 AN: 31980

Ashkenazi Jewish (ASJ) AF: 0.00194 AC: 46 AN: 23706

East Asian (EAS) AF: 0.00 AC: 0 AN: 31042

South Asian (SAS) AF: 0.00647 AC: 489 AN: 75594

European-Finnish (FIN) AF: 0.000459 AC: 22 AN: 47956

Middle Eastern (MID) AF: 0.00130 AC: 7 AN: 5404

European-Non Finnish (NFE) AF: 0.000248 AC: 262 AN: 1058280

Other (OTH) AF: 0.000949 AC: 53 AN: 55836

GnomAD4 genome AF: 0.000514 AC: 78 AN: 151622 Hom.: 0 Cov.: 32 AF XY: 0.000432 AC XY: 32 AN XY: 74152

African (AFR) AF: 0.00 AC: 0 AN: 41164

American (AMR) AF: 0.0000655 AC: 1 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.00642 AC: 31 AN: 4830

European-Finnish (FIN) AF: 0.000284 AC: 3 AN: 10554

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.000442 AC: 30 AN: 67896

Other (OTH) AF: 0.000475 AC: 1 AN: 2104

Alfa AF: 0.000555 Hom.: 0

Bravo AF: 0.000329

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Nov 19, 2015

GeneDx

Significance: Likely 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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	18
DANN	Benign	0.89
PhyloP100		2.7
PromoterAI		0.0072	Neutral

Splicing

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

Other links and lift over

dbSNP: rs550163684; hg19: chr20-47538400; COSMIC: COSV105927441;