3-134250593-AG-AGG

Variant names:

• chr3-134250593-A-AG
• rs587770426
• NM_002958.4:c.61dupC

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002958.4(RYK):​c.61dupC​(p.Leu21ProfsTer60) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: RYK NM_002958.4 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.656
• Publications: 5 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002958.4. 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
	RYK	NM_002958.4	MANE Select	c.61dupC	p.Leu21ProfsTer60	frameshift	Exon 1 of 15	NP_002949.2	P34925-1
	RYK	NM_001005861.3		c.61dupC	p.Leu21ProfsTer60	frameshift	Exon 1 of 15	NP_001005861.1	P34925-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYK	ENST00000623711.4	TSL:1 MANE Select	c.61dupC	p.Leu21ProfsTer60	frameshift	Exon 1 of 15	ENSP00000485095.1	P34925-1
	RYK	ENST00000620660.4	TSL:1	c.61dupC	p.Leu21ProfsTer60	frameshift	Exon 1 of 15	ENSP00000478721.1	P34925-2
	RYK	ENST00000946535.1		c.61dupC	p.Leu21ProfsTer60	frameshift	Exon 1 of 16	ENSP00000616594.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 1.00 AC: 4 AN: 4 AF XY: 1.00

Gnomad NFE exome AF: 1.00

GnomAD4 exome Cov.: 16

GnomAD4 genome Cov.: 31

Alfa AF: 1.00 Hom.: 2231

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.66

Splicing

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

Other links and lift over

dbSNP: rs587770426; hg19: chr3-133969437; COSMIC: COSV56062880; COSMIC: COSV56062880;