3-134250569-AGCGGCGGCG-AGCGGCGGCGGCG

Variant names:

• chr3-134250569-A-AGCG
• rs1284777873
• NM_002958.4:c.83_85dupCGC

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP3 BS2

The NM_002958.4(RYK):​c.83_85dupCGC​(p.Pro28dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000337 in 1,078,554 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00095 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00024 (1 hom.)
• Consequence: RYK NM_002958.4 conservative_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.28

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 Likely_benign. Variant got -5 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_002958.4
• BS2: High AC in GnomAd4 at 141 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYK	NM_002958.4	c.83_85dupCGC	p.Pro28dup	conservative_inframe_insertion	Exon 1 of 15	ENST00000623711.4	NP_002949.2
RYK	NM_001005861.3	c.83_85dupCGC	p.Pro28dup	conservative_inframe_insertion	Exon 1 of 15		NP_001005861.1
RYK	XR_007095716.1	n.288_290dupCGC		non_coding_transcript_exon_variant	Exon 1 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYK	ENST00000623711.4	c.83_85dupCGC	p.Pro28dup	conservative_inframe_insertion	Exon 1 of 15	1	NM_002958.4	ENSP00000485095.1
RYK	ENST00000620660.4	c.83_85dupCGC	p.Pro28dup	conservative_inframe_insertion	Exon 1 of 15	1		ENSP00000478721.1

Frequencies

GnomAD3 genomes AF: 0.000950 AC: 141 AN: 148412 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000334

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00566

Gnomad SAS AF: 0.00146

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000360

Gnomad OTH AF: 0.000977

GnomAD4 exome AF: 0.000239 AC: 222 AN: 930034 Hom.: 1 Cov.: 13 AF XY: 0.000232 AC XY: 102 AN XY: 440560

Gnomad4 AFR exome AF: 0.000880

Gnomad4 AMR exome AF: 0.000165

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00185

Gnomad4 SAS exome AF: 0.00121

Gnomad4 FIN exome AF: 0.0000561

Gnomad4 NFE exome AF: 0.000142

Gnomad4 OTH exome AF: 0.000782

GnomAD4 genome AF: 0.000949 AC: 141 AN: 148520 Hom.: 0 Cov.: 30 AF XY: 0.000953 AC XY: 69 AN XY: 72414

Gnomad4 AFR AF: 0.00181

Gnomad4 AMR AF: 0.000334

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00568

Gnomad4 SAS AF: 0.00146

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000360

Gnomad4 OTH AF: 0.000966

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1284777873; hg19: chr3-133969413;