chr17-32488418-C-T

Variant names:

• chr17-32488418-C-T
• rs34511797
• NM_003885.3:c.798C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003885.3(CDK5R1):​c.798C>T​(p.Asn266Asn) 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, multiple submitters, no conflicts B:2
• 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

Our verdict: Benign. The variant received -21 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_multiple_submitters_no_conflicts, 2 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 the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High AC in GnomAd4 at 765 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK5R1	NM_003885.3	c.798C>T	p.Asn266Asn	synonymous_variant	Exon 2 of 2	ENST00000313401.4	NP_003876.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK5R1	ENST00000313401.4	c.798C>T	p.Asn266Asn	synonymous_variant	Exon 2 of 2	1	NM_003885.3	ENSP00000318486.3
CDK5R1	ENST00000584716.1	n.*116C>T		non_coding_transcript_exon_variant	Exon 2 of 3	1		ENSP00000463654.1
CDK5R1	ENST00000584716.1	n.*116C>T		3_prime_UTR_variant	Exon 2 of 3	1		ENSP00000463654.1
CDK5R1	ENST00000584792.5	c.*116C>T		3_prime_UTR_variant	Exon 2 of 2	2		ENSP00000464129.1

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

GnomAD2 exomes AF: 0.00151 AC: 380 AN: 251494 AF XY: 0.00115

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 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 AC: 534 AN: 33480

Gnomad4 AMR exome AF: 0.00165 AC: 74 AN: 44724

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26136

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39700

Gnomad4 SAS exome AF: 0.0000696 AC: 6 AN: 86258

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53416

Gnomad4 NFE exome AF: 0.0000558 AC: 62 AN: 1112010

Gnomad4 Remaining exome AF: 0.00137 AC: 83 AN: 60394

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 AC: 0.0170553 AN: 0.0170553

Gnomad4 AMR AF: 0.00262 AC: 0.00261814 AN: 0.00261814

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000147 AC: 0.000147042 AN: 0.000147042

Gnomad4 OTH AF: 0.00332 AC: 0.00332068 AN: 0.00332068

Alfa AF: 0.00247 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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 13, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	13
DANN	Benign	0.86
Mutation Taster		=100/0	polymorphism

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;