20-48921796-C-T

Variant names:

• chr20-48921796-C-T
• rs2273101
• NM_006420.3:c.-94C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006420.3(ARFGEF2):​c.-94C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 1,178,504 control chromosomes in the GnomAD database, including 31,952 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2571 hom., cov: 32)
  • Exomes 𝑓: 0.23 (29381 hom.)
• Consequence: ARFGEF2 NM_006420.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.328
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 20-48921796-C-T is Benign according to our data. Variant chr20-48921796-C-T is described in ClinVar as Benign. ClinVar VariationId is 338676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.235 is higher than 0.05.

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.-94C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 39	NP_006411.2	Q9Y6D5
	ARFGEF2	NM_006420.3	MANE Select	c.-94C>T		5_prime_UTR	Exon 1 of 39	NP_006411.2	Q9Y6D5
	ARFGEF2	NM_001410846.1		c.-94C>T		5_prime_UTR_premature_start_codon_gain	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.-94C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 39	ENSP00000360985.4	Q9Y6D5
	ARFGEF2	ENST00000371917.5	TSL:1 MANE Select	c.-94C>T		5_prime_UTR	Exon 1 of 39	ENSP00000360985.4	Q9Y6D5
	ARFGEF2	ENST00000939861.1		c.-94C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 39	ENSP00000609920.1

Frequencies

GnomAD3 genomes AF: 0.161 AC: 24348 AN: 151592 Hom.: 2570 Cov.: 32

Gnomad AFR AF: 0.0412

Gnomad AMI AF: 0.419

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.154

Gnomad EAS AF: 0.0503

Gnomad SAS AF: 0.0853

Gnomad FIN AF: 0.226

Gnomad MID AF: 0.121

Gnomad NFE AF: 0.238

Gnomad OTH AF: 0.135

GnomAD4 exome AF: 0.234 AC: 240303 AN: 1026804 Hom.: 29381 AF XY: 0.234 AC XY: 114387 AN XY: 488646

African (AFR) AF: 0.0293 AC: 581 AN: 19856

American (AMR) AF: 0.163 AC: 964 AN: 5920

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 1864 AN: 10904

East Asian (EAS) AF: 0.0853 AC: 1599 AN: 18736

South Asian (SAS) AF: 0.0915 AC: 1876 AN: 20508

European-Finnish (FIN) AF: 0.235 AC: 7059 AN: 30050

Middle Eastern (MID) AF: 0.136 AC: 393 AN: 2882

European-Non Finnish (NFE) AF: 0.248 AC: 218296 AN: 879318

Other (OTH) AF: 0.199 AC: 7671 AN: 38630

GnomAD4 genome AF: 0.161 AC: 24350 AN: 151700 Hom.: 2571 Cov.: 32 AF XY: 0.156 AC XY: 11601 AN XY: 74172

African (AFR) AF: 0.0411 AC: 1706 AN: 41484

American (AMR) AF: 0.145 AC: 2207 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.154 AC: 534 AN: 3470

East Asian (EAS) AF: 0.0502 AC: 258 AN: 5136

South Asian (SAS) AF: 0.0860 AC: 414 AN: 4816

European-Finnish (FIN) AF: 0.226 AC: 2367 AN: 10460

Middle Eastern (MID) AF: 0.123 AC: 36 AN: 292

European-Non Finnish (NFE) AF: 0.238 AC: 16160 AN: 67794

Other (OTH) AF: 0.136 AC: 286 AN: 2108

Alfa AF: 0.146 Hom.: 397

Bravo AF: 0.149

Asia WGS AF: 0.0880 AC: 304 AN: 3462

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Periventricular heterotopia with microcephaly, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	13
DANN	Benign	0.90
PhyloP100		-0.33
PromoterAI		-0.016	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs2273101; hg19: chr20-47538333;