Genetic Variant RYK:c.1102+2850A>G (chr3-134185987-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002958.4(RYK):c.1102+2850A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.262 in 152,064 control chromosomes in the GnomAD database, including 5,780 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.26 ( 5780 hom., cov: 32)

Consequence

RYK
NM_002958.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.177

Publications

2 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.7).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.327 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
RYK	NM_002958.4 link	c.1102+2850A>G	intron_variant	Intron 9 of 14	ENST00000623711.4	NP_002949.2
RYK	NM_001005861.3 link	c.1111+2850A>G	intron_variant	Intron 9 of 14		NP_001005861.1
RYK	XR_007095716.1 link	n.1316+2850A>G	intron_variant	Intron 9 of 11

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
RYK	ENST00000623711.4 link	c.1102+2850A>G	intron_variant	Intron 9 of 14	1	NM_002958.4	ENSP00000485095.1
RYK	ENST00000620660.4 link	c.1111+2850A>G	intron_variant	Intron 9 of 14	1		ENSP00000478721.1
RYK	ENST00000480381.1 link	n.471+2850A>G	intron_variant	Intron 3 of 3	5
RYK	ENST00000486725.1 link	n.154+2850A>G	intron_variant	Intron 2 of 5	2		ENSP00000417836.1

Frequencies

GnomAD3 genomes

AF:

0.262

AC:

39746

AN:

151946

Hom.:

5777

Cov.:

show subpopulations

Gnomad AFR

AF:

0.213

Gnomad AMI

AF:

0.422

Gnomad AMR

AF:

0.225

Gnomad ASJ

AF:

0.210

Gnomad EAS

AF:

0.00751

Gnomad SAS

AF:

0.0677

Gnomad FIN

AF:

0.287

Gnomad MID

AF:

0.117

Gnomad NFE

AF:

0.331

Gnomad OTH

AF:

0.240

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.262

AC:

39778

AN:

152064

Hom.:

5780

Cov.:

AF XY:

0.253

AC XY:

18840

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.213

AC:

8838

AN:

41496

American (AMR)

AF:

0.225

AC:

3437

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.210

AC:

727

AN:

3468

East Asian (EAS)

AF:

0.00753

AC:

AN:

5182

South Asian (SAS)

AF:

0.0669

AC:

323

AN:

4826

European-Finnish (FIN)

AF:

0.287

AC:

3036

AN:

10564

Middle Eastern (MID)

AF:

0.126

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.331

AC:

22453

AN:

67926

Other (OTH)

AF:

0.239

AC:

503

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1458

2916

4373

5831

7289

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

394

788

1182

1576

1970

<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:

0.205

Hom.:

611

Bravo

AF:

0.257

Asia WGS

AF:

0.0560

AC:

196

AN:

3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

(source)

DANN

Benign

0.88

PhyloP100

0.18

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over