Genetic Variant NM_002958.4:c.80_85dupCGCCGC (chr3-134250569-A-AGCGGCG) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP3BP6_ModerateBA1

The NM_002958.4(RYK):c.80_85dupCGCCGC(p.Pro27_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 0.00306 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 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 1.28

Variant links:

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]

RYK links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 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_single_submitter, 1 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 rank	MANE	Protein	UniProt
RYK	NM_002958.4 link	c.80_85dupCGCCGC	p.Pro27_Pro28dup	conservative_inframe_insertion	Exon 1 of 15	ENST00000623711.4	NP_002949.2	P34925-1Q59FQ5Q8WTZ8
RYK	NM_001005861.3 link	c.80_85dupCGCCGC	p.Pro27_Pro28dup	conservative_inframe_insertion	Exon 1 of 15		NP_001005861.1	P34925-2Q59FQ5Q8WTZ8
RYK	XR_007095716.1 link	n.285_290dupCGCCGC		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 link	c.80_85dupCGCCGC	p.Pro27_Pro28dup	conservative_inframe_insertion	Exon 1 of 15	1	NM_002958.4	ENSP00000485095.1		P34925-1
RYK	ENST00000620660.4 link	c.80_85dupCGCCGC	p.Pro27_Pro28dup	conservative_inframe_insertion	Exon 1 of 15	1		ENSP00000478721.1		P34925-2

Frequencies

GnomAD3 genomes

AF:

0.0169

AC:

2506

AN:

148398

Hom.:

Cov.:

show subpopulations

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.:

Cov.:

AF XY:

0.000779

AC XY:

343

AN XY:

440558

show subpopulations

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.:

Cov.:

AF XY:

0.0164

AC XY:

1184

AN XY:

72412

show subpopulations

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, single submitter

LINK: link

Submissions by phenotype

RYK-related disorder

Benign:1

Dec 20, 2023

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Jun 27, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over