Genetic Variant RYK:p.Pro28dup (chr3-134250569-A-AGCG) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP3BS2

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

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.28

Publications

0 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_002958.4

BS2

High AC in GnomAd4 at 141 AD gene.

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.83_85dupCGC	p.Pro28dup	conservative_inframe_insertion	Exon 1 of 15	NP_002949.2	P34925-1
	RYK	NM_001005861.3		c.83_85dupCGC	p.Pro28dup	conservative_inframe_insertion	Exon 1 of 15	NP_001005861.1	P34925-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RYK	ENST00000623711.4	TSL:1 MANE Select	c.83_85dupCGC	p.Pro28dup	conservative_inframe_insertion	Exon 1 of 15	ENSP00000485095.1	P34925-1
RYK	ENST00000620660.4	TSL:1	c.83_85dupCGC	p.Pro28dup	conservative_inframe_insertion	Exon 1 of 15	ENSP00000478721.1	P34925-2
RYK	ENST00000946535.1		c.83_85dupCGC	p.Pro28dup	conservative_inframe_insertion	Exon 1 of 16	ENSP00000616594.1

Frequencies

GnomAD3 genomes

AF:

0.000950

AC:

141

AN:

148412

Hom.:

Cov.:

show subpopulations

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.:

Cov.:

AF XY:

0.000232

AC XY:

102

AN XY:

440560

show subpopulations

African (AFR)

AF:

0.000880

AC:

AN:

18186

American (AMR)

AF:

0.000165

AC:

AN:

6072

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

10796

East Asian (EAS)

AF:

0.00185

AC:

AN:

21082

South Asian (SAS)

AF:

0.00121

AC:

AN:

17362

European-Finnish (FIN)

AF:

0.0000561

AC:

AN:

17810

Middle Eastern (MID)

AF:

0.000829

AC:

AN:

2414

European-Non Finnish (NFE)

AF:

0.000142

AC:

114

AN:

800516

Other (OTH)

AF:

0.000782

AC:

AN:

35796

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000949

AC:

141

AN:

148520

Hom.:

Cov.:

AF XY:

0.000953

AC XY:

AN XY:

72414

show subpopulations

African (AFR)

AF:

0.00181

AC:

AN:

40994

American (AMR)

AF:

0.000334

AC:

AN:

14990

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3422

East Asian (EAS)

AF:

0.00568

AC:

AN:

5108

South Asian (SAS)

AF:

0.00146

AC:

AN:

4790

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9218

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000360

AC:

AN:

66726

Other (OTH)

AF:

0.000966

AC:

AN:

2070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.3

Mutation Taster

=300/0

polymorphism

(source)

Splicing

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

Publications

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3-134250569-AGCGGCGGCG-AGCGGCGGCGGCG

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over