NM_002958.4:c.149C>T

Variant names:

• chr3-134250506-G-A
• rs2015586744
• NM_002958.4:c.149C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_002958.4(RYK):​c.149C>T​(p.Pro50Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000726 in 1,101,768 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000073 (1 hom.)
• Consequence: RYK NM_002958.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.399
• Publications: 0 publications found

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

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15910873).
• BP6: Variant 3-134250506-G-A is Benign according to our data. Variant chr3-134250506-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3034688.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 8 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.149C>T	p.Pro50Leu	missense	Exon 1 of 15	NP_002949.2	P34925-1
	RYK	NM_001005861.3		c.149C>T	p.Pro50Leu	missense	Exon 1 of 15	NP_001005861.1	P34925-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYK	ENST00000623711.4	TSL:1 MANE Select	c.149C>T	p.Pro50Leu	missense	Exon 1 of 15	ENSP00000485095.1	P34925-1
	RYK	ENST00000620660.4	TSL:1	c.149C>T	p.Pro50Leu	missense	Exon 1 of 15	ENSP00000478721.1	P34925-2
	RYK	ENST00000946535.1		c.149C>T	p.Pro50Leu	missense	Exon 1 of 16	ENSP00000616594.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000726 AC: 8 AN: 1101768 Hom.: 1 Cov.: 26 AF XY: 0.00000378 AC XY: 2 AN XY: 529800

African (AFR) AF: 0.00 AC: 0 AN: 22588

American (AMR) AF: 0.000102 AC: 1 AN: 9828

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15096

East Asian (EAS) AF: 0.00 AC: 0 AN: 25652

South Asian (SAS) AF: 0.00 AC: 0 AN: 28896

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22722

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2968

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 930364

Other (OTH) AF: 0.000160 AC: 7 AN: 43654

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	RYK-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.40
PrimateAI	Pathogenic	0.83	D
Sift4G	Pathogenic	0.0	D
Vest4		0.19
MVP		0.36
ClinPred		0.79	D
GERP RS		-3.5
PromoterAI		0.077	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.4
Varity_R		0.040
gMVP		0.30
Mutation Taster		=300/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs2015586744; hg19: chr3-133969350;