rs12186098

chr3-134154203-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000484106.3(RYK):c.435+21406C>T variant causes a intron, NMD transcript change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0448 in 152,276 control chromosomes in the GnomAD database, including 187 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 0.045 (187 hom., cov: 32)
• Consequence: RYK ENST00000484106.3 intron, NMD_transcript
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0930

Genes affected

RYK (HGNC:10481): (receptor like tyrosine kinase) The protein encoded by this gene is an atypical member of the family of growth factor receptor protein tyrosine kinases, differing from other members at a number of conserved residues in the activation and nucleotide binding domains. This gene product belongs to a subfamily whose members do not appear to be regulated by phosphorylation in the activation segment. It has been suggested that mediation of biological activity by recruitment of a signaling-competent auxiliary protein may occur through an as yet uncharacterized mechanism. The encoded protein has a leucine-rich extracellular domain with a WIF-type Wnt binding region, a single transmembrane domain, and an intracellular tyrosine kinase domain. This protein is involved in stimulating Wnt signaling pathways such as the regulation of axon pathfinding. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Feb 2012]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYK	ENST00000484106.3	c.435+21406C>T		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0448 AC: 6818 AN: 152158 Hom.: 186 Cov.: 32

Gnomad AFR AF: 0.0318

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.0558

Gnomad ASJ AF: 0.0288

Gnomad EAS AF: 0.119

Gnomad SAS AF: 0.0476

Gnomad FIN AF: 0.0435

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0446

Gnomad OTH AF: 0.0592

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

GnomAD4 genome AF: 0.0448 AC: 6827 AN: 152276 Hom.: 187 Cov.: 32 AF XY: 0.0445 AC XY: 3312 AN XY: 74458

Gnomad4 AFR AF: 0.0318

Gnomad4 AMR AF: 0.0560

Gnomad4 ASJ AF: 0.0288

Gnomad4 EAS AF: 0.119

Gnomad4 SAS AF: 0.0481

Gnomad4 FIN AF: 0.0435

Gnomad4 NFE AF: 0.0446

Gnomad4 OTH AF: 0.0586

Alfa AF: 0.0442 Hom.: 15

Bravo AF: 0.0478

Asia WGS AF: 0.0810 AC: 283 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	6.6
Dann	Benign	0.70

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs12186098; hg19: chr3-133873047; COSMIC: COSV56061949;