chr17-32487661-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003885.3(CDK5R1):​c.41C>T​(p.Ala14Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

CDK5R1
NM_003885.3 missense

Scores

1
11
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.43
Variant links:
Genes affected
CDK5R1 (HGNC:1775): (cyclin dependent kinase 5 regulatory subunit 1) The protein encoded by this gene (p35) is a neuron-specific activator of cyclin-dependent kinase 5 (CDK5); the activation of CDK5 is required for proper development of the central nervous system. The p35 form of this protein is proteolytically cleaved by calpain, generating a p25 form. The cleavage of p35 into p25 results in relocalization of the protein from the cell periphery to nuclear and perinuclear regions. P25 deregulates CDK5 activity by prolonging its activation and changing its cellular location. The p25 form accumulates in the brain neurons of patients with Alzheimer's disease. This accumulation correlates with an increase in CDK5 kinase activity, and may lead to aberrantly phosphorylated forms of the microtubule-associated protein tau, which contributes to Alzheimer's disease. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CDK5R1NM_003885.3 linkuse as main transcriptc.41C>T p.Ala14Val missense_variant 2/2 ENST00000313401.4 NP_003876.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CDK5R1ENST00000313401.4 linkuse as main transcriptc.41C>T p.Ala14Val missense_variant 2/21 NM_003885.3 ENSP00000318486 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJan 03, 2024The c.41C>T (p.A14V) alteration is located in exon 2 (coding exon 1) of the CDK5R1 gene. This alteration results from a C to T substitution at nucleotide position 41, causing the alanine (A) at amino acid position 14 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.27
BayesDel_addAF
Benign
0.0058
T
BayesDel_noAF
Benign
-0.23
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Benign
0.36
T
Eigen
Uncertain
0.35
Eigen_PC
Uncertain
0.37
FATHMM_MKL
Benign
0.68
D
LIST_S2
Uncertain
0.93
D
M_CAP
Pathogenic
0.48
D
MetaRNN
Uncertain
0.57
D
MetaSVM
Uncertain
-0.063
T
MutationAssessor
Uncertain
2.4
M
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.74
T
PROVEAN
Benign
-2.3
N
REVEL
Uncertain
0.52
Sift
Uncertain
0.0090
D
Sift4G
Uncertain
0.034
D
Polyphen
0.75
P
Vest4
0.32
MutPred
0.66
Gain of sheet (P = 0.0028);
MVP
0.71
MPC
1.8
ClinPred
0.98
D
GERP RS
4.2
Varity_R
0.52
gMVP
0.63

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-30814679; API