Genetic Variant NM_002958.4:c.77_85dupCGCCGCCGC (chr3-134250569-A-AGCGGCGGCG) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP3BS2

The NM_002958.4(RYK):c.77_85dupCGCCGCCGC(p.Pro26_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 0.0000501 in 1,078,574 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

RYK
NM_002958.4 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

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 Likely_benign. Variant got -5 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_002958.4

BS2

High AC in GnomAd4 at 39 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYK	NM_002958.4 link	c.77_85dupCGCCGCCGC	p.Pro26_Pro28dup	conservative_inframe_insertion	Exon 1 of 15	ENST00000623711.4	NP_002949.2	P34925-1Q59FQ5Q8WTZ8
RYK	NM_001005861.3 link	c.77_85dupCGCCGCCGC	p.Pro26_Pro28dup	conservative_inframe_insertion	Exon 1 of 15		NP_001005861.1	P34925-2Q59FQ5Q8WTZ8
RYK	XR_007095716.1 link	n.282_290dupCGCCGCCGC		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.77_85dupCGCCGCCGC	p.Pro26_Pro28dup	conservative_inframe_insertion	Exon 1 of 15	1	NM_002958.4	ENSP00000485095.1		P34925-1
RYK	ENST00000620660.4 link	c.77_85dupCGCCGCCGC	p.Pro26_Pro28dup	conservative_inframe_insertion	Exon 1 of 15	1		ENSP00000478721.1		P34925-2

Frequencies

GnomAD3 genomes

AF:

0.000263

AC:

AN:

148414

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000954

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000161

AC:

AN:

930052

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

440568

show subpopulations

Gnomad4 AFR exome

AF:

0.000550

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000375

Gnomad4 OTH exome

AF:

0.0000559

GnomAD4 genome

AF:

0.000263

AC:

AN:

148522

Hom.:

Cov.:

AF XY:

0.000262

AC XY:

AN XY:

72416

show subpopulations

Gnomad4 AFR

AF:

0.000951

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over