3-134250569-A-AGCGGCG

Position:

• chr3-134250569-A-AGCGGCG

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BA1

The NM_002958.4(RYK):​c.85_86insCGCCGC​(p.Pro27_Pro28dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00306 in 1,078,532 control chromosomes in the GnomAD database, including 65 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (45 hom., cov: 30)
  • Exomes 𝑓: 0.00085 (20 hom.)
• Consequence: RYK NM_002958.4 inframe_insertion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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 Benign. Variant got -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_002958.4
• BP6: Variant 3-134250569-A-AGCGGCG is Benign according to our data. Variant chr3-134250569-A-AGCGGCG is described in ClinVar as [Benign]. Clinvar id is 780896.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0565 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYK	NM_002958.4	c.85_86insCGCCGC	p.Pro27_Pro28dup	inframe_insertion	1/15	ENST00000623711.4
RYK	NM_001005861.3	c.85_86insCGCCGC	p.Pro27_Pro28dup	inframe_insertion	1/15
RYK	XR_007095716.1	n.290_291insCGCCGC		non_coding_transcript_exon_variant	1/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYK	ENST00000623711.4	c.85_86insCGCCGC	p.Pro27_Pro28dup	inframe_insertion	1/15	1	NM_002958.4	A2
RYK	ENST00000620660.4	c.85_86insCGCCGC	p.Pro27_Pro28dup	inframe_insertion	1/15	1		P4

Frequencies

GnomAD3 genomes AF: 0.0169 AC: 2506 AN: 148398 Hom.: 44 Cov.: 30

Gnomad AFR AF: 0.0585

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00528

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000165

Gnomad OTH AF: 0.0107

GnomAD4 exome AF: 0.000846 AC: 787 AN: 930026 Hom.: 20 Cov.: 13 AF XY: 0.000779 AC XY: 343 AN XY: 440558

Gnomad4 AFR exome AF: 0.0347

Gnomad4 AMR exome AF: 0.00198

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000576

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000899

Gnomad4 OTH exome AF: 0.00198

GnomAD4 genome AF: 0.0169 AC: 2511 AN: 148506 Hom.: 45 Cov.: 30 AF XY: 0.0164 AC XY: 1184 AN XY: 72412

Gnomad4 AFR AF: 0.0585

Gnomad4 AMR AF: 0.00527

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000196

Gnomad4 SAS AF: 0.000209

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000165

Gnomad4 OTH AF: 0.0106

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

RYK-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 20, 2023

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 27, 2018

- -

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;