chr2-172799881-G-A

Variant names:

• chr2-172799881-G-A
• rs2161994
• NM_007023.4:c.297+2268G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_007023.4(RAPGEF4):​c.297+2268G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.313 in 152,008 control chromosomes in the GnomAD database, including 7,609 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.31 (7609 hom., cov: 32)
• Consequence: RAPGEF4 NM_007023.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.65
• Publications: 3 publications found

Genes affected

RAPGEF4 (HGNC:16626): (Rap guanine nucleotide exchange factor 4) Enables guanyl-nucleotide exchange factor activity. Predicted to be involved in regulation of neurotransmitter receptor localization to postsynaptic specialization membrane and regulation of postsynapse organization. Predicted to act upstream of or within adenylate cyclase-activating G protein-coupled receptor signaling pathway; regulation of exocytosis; and secretion by cell. Predicted to be located in plasma membrane. Predicted to be active in glutamatergic synapse; hippocampal mossy fiber to CA3 synapse; and postsynaptic density. Implicated in autistic disorder. [provided by Alliance of Genome Resources, Apr 2022]

RAPGEF4 Gene-Disease associations (from GenCC):

• prostate cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.452 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAPGEF4	NM_007023.4	c.297+2268G>A		intron_variant	Intron 3 of 30	ENST00000397081.8	NP_008954.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAPGEF4	ENST00000397081.8	c.297+2268G>A		intron_variant	Intron 3 of 30	1	NM_007023.4	ENSP00000380271.3
RAPGEF4	ENST00000409036.5	c.297+2268G>A		intron_variant	Intron 3 of 27	5		ENSP00000387104.1
RAPGEF4	ENST00000464976.1	n.518+2268G>A		intron_variant	Intron 3 of 3	1
RAPGEF4	ENST00000484331.5	n.364+2268G>A		intron_variant	Intron 3 of 4	4

Frequencies

GnomAD3 genomes AF: 0.313 AC: 47512 AN: 151890 Hom.: 7600 Cov.: 32

Gnomad AFR AF: 0.318

Gnomad AMI AF: 0.373

Gnomad AMR AF: 0.344

Gnomad ASJ AF: 0.248

Gnomad EAS AF: 0.467

Gnomad SAS AF: 0.365

Gnomad FIN AF: 0.332

Gnomad MID AF: 0.274

Gnomad NFE AF: 0.287

Gnomad OTH AF: 0.307

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.313 AC: 47547 AN: 152008 Hom.: 7609 Cov.: 32 AF XY: 0.317 AC XY: 23536 AN XY: 74286

African (AFR) AF: 0.318 AC: 13192 AN: 41456

American (AMR) AF: 0.344 AC: 5250 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.248 AC: 859 AN: 3470

East Asian (EAS) AF: 0.467 AC: 2415 AN: 5168

South Asian (SAS) AF: 0.366 AC: 1760 AN: 4806

European-Finnish (FIN) AF: 0.332 AC: 3501 AN: 10556

Middle Eastern (MID) AF: 0.264 AC: 77 AN: 292

European-Non Finnish (NFE) AF: 0.287 AC: 19513 AN: 67974

Other (OTH) AF: 0.304 AC: 640 AN: 2108

Alfa AF: 0.294 Hom.: 22531

Bravo AF: 0.313

Asia WGS AF: 0.397 AC: 1381 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	13
DANN	Benign	0.44
PhyloP100		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs2161994; hg19: chr2-173664609;