rs149172723

Variant names:

• chr20-48953759-C-T
• rs149172723
• NM_006420.3:c.807C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_006420.3(ARFGEF2):​c.807C>T​(p.Asp269Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00406 in 1,614,020 control chromosomes in the GnomAD database, including 21 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 0.0023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (21 hom.)
• Consequence: ARFGEF2 NM_006420.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: -6.87
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 20-48953759-C-T is Benign according to our data. Variant chr20-48953759-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 128445.
• BP7: Synonymous conserved (PhyloP=-6.87 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00232 (353/152208) while in subpopulation NFE AF = 0.00371 (252/68010). AF 95% confidence interval is 0.00333. There are 0 homozygotes in GnomAd4. There are 148 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 21 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.807C>T	p.Asp269Asp	synonymous	Exon 6 of 39	NP_006411.2	Q9Y6D5
	ARFGEF2	NM_001410846.1		c.807C>T	p.Asp269Asp	synonymous	Exon 6 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.807C>T	p.Asp269Asp	synonymous	Exon 6 of 39	ENSP00000360985.4	Q9Y6D5
	ARFGEF2	ENST00000679436.1		c.807C>T	p.Asp269Asp	synonymous	Exon 6 of 39	ENSP00000504888.1	A0A7P0T7Z2
	ARFGEF2	ENST00000939861.1		c.807C>T	p.Asp269Asp	synonymous	Exon 6 of 39	ENSP00000609920.1

Frequencies

GnomAD3 genomes AF: 0.00232 AC: 353 AN: 152090 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000990

Gnomad AMI AF: 0.0220

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00270

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00370

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00222 AC: 557 AN: 251076 AF XY: 0.00229

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.00341

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00424 AC: 6205 AN: 1461812 Hom.: 21 Cov.: 31 AF XY: 0.00419 AC XY: 3048 AN XY: 727204

African (AFR) AF: 0.000627 AC: 21 AN: 33478

American (AMR) AF: 0.00141 AC: 63 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00278 AC: 240 AN: 86246

European-Finnish (FIN) AF: 0.000468 AC: 25 AN: 53416

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00497 AC: 5529 AN: 1111974

Other (OTH) AF: 0.00533 AC: 322 AN: 60390

GnomAD4 genome AF: 0.00232 AC: 353 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.00199 AC XY: 148 AN XY: 74410

African (AFR) AF: 0.000987 AC: 41 AN: 41540

American (AMR) AF: 0.00144 AC: 22 AN: 15294

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.00270 AC: 13 AN: 4818

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10590

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

European-Non Finnish (NFE) AF: 0.00371 AC: 252 AN: 68010

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00249 Hom.: 0

Bravo AF: 0.00254

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00354

EpiControl AF: 0.00368

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	3	not specified (3)
-	1	1	Periventricular heterotopia with microcephaly, autosomal recessive (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.089
DANN	Benign	0.54
PhyloP100		-6.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs149172723; hg19: chr20-47570296;