17-32488418-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_003885.3(CDK5R1):c.798C>T(p.Asn266=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000952 in 1,614,096 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0050 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (6 hom.)
• Consequence: CDK5R1 NM_003885.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.918

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 17-32488418-C-T is Benign according to our data. Variant chr17-32488418-C-T is described in ClinVar as [Benign]. Clinvar id is 784742.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.918 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00503 (765/152210) while in subpopulation AFR AF= 0.0171 (708/41512). AF 95% confidence interval is 0.016. There are 5 homozygotes in gnomad4. There are 383 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 764 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDK5R1	NM_003885.3	c.798C>T	p.Asn266=	synonymous_variant	2/2	ENST00000313401.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDK5R1	ENST00000313401.4	c.798C>T	p.Asn266=	synonymous_variant	2/2	1	NM_003885.3	P1
CDK5R1	ENST00000584716.1	c.*116C>T		3_prime_UTR_variant, NMD_transcript_variant	2/3	1
CDK5R1	ENST00000584792.5	c.*116C>T		3_prime_UTR_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.00502 AC: 764 AN: 152092 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

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: 0.000147

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.00151 AC: 380 AN: 251494 Hom.: 2 AF XY: 0.00115 AC XY: 156 AN XY: 135922

Gnomad AFR exome AF: 0.0181

Gnomad AMR exome AF: 0.00173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000527 AC: 771 AN: 1461886 Hom.: 6 Cov.: 32 AF XY: 0.000480 AC XY: 349 AN XY: 727244

Gnomad4 AFR exome AF: 0.0159

Gnomad4 AMR exome AF: 0.00165

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000558

Gnomad4 OTH exome AF: 0.00137

GnomAD4 genome AF: 0.00503 AC: 765 AN: 152210 Hom.: 5 Cov.: 32 AF XY: 0.00515 AC XY: 383 AN XY: 74440

Gnomad4 AFR AF: 0.0171

Gnomad4 AMR AF: 0.00262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00274 Hom.: 1

Bravo AF: 0.00559

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 13, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
Cadd	Benign	13
Dann	Benign	0.86

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

LitVar

Other links and lift over

dbSNP: rs34511797; hg19: chr17-30815436;