rs2161994

Positions:

• chr2-172799881-G-A
• chr2-172799881-G-C

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
RAPGEF4	NM_007023.4	c.297+2268G>A		intron_variant		ENST00000397081.8	NP_008954.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAPGEF4	ENST00000397081.8	c.297+2268G>A		intron_variant		1	NM_007023.4	ENSP00000380271	P1
RAPGEF4	ENST00000464976.1	n.518+2268G>A		intron_variant, non_coding_transcript_variant		1
RAPGEF4	ENST00000409036.5	c.297+2268G>A		intron_variant		5		ENSP00000387104
RAPGEF4	ENST00000484331.5	n.364+2268G>A		intron_variant, non_coding_transcript_variant		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

Gnomad4 AFR AF: 0.318

Gnomad4 AMR AF: 0.344

Gnomad4 ASJ AF: 0.248

Gnomad4 EAS AF: 0.467

Gnomad4 SAS AF: 0.366

Gnomad4 FIN AF: 0.332

Gnomad4 NFE AF: 0.287

Gnomad4 OTH AF: 0.304

Alfa AF: 0.290 Hom.: 13260

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs2161994; hg19: chr2-173664609;