7-151054004-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004935.4(CDK5):c.*5C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00083 in 1,582,692 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00079 (19 hom.)
• Consequence: CDK5 NM_004935.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.30

Genes affected

CDK5 (HGNC:1774): (cyclin dependent kinase 5) This gene encodes a proline-directed serine/threonine kinase that is a member of the cyclin-dependent kinase family of proteins. Unlike other members of the family, the protein encoded by this gene does not directly control cell cycle regulation. Instead the protein, which is predominantly expressed at high levels in mammalian postmitotic central nervous system neurons, functions in diverse processes such as synaptic plasticity and neuronal migration through phosphorylation of proteins required for cytoskeletal organization, endocytosis and exocytosis, and apoptosis. In humans, an allelic variant of the gene that results in undetectable levels of the protein has been associated with lethal autosomal recessive lissencephaly-7. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2015]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 7-151054004-G-A is Benign according to our data. Variant chr7-151054004-G-A is described in ClinVar as [Benign]. Clinvar id is 3037340.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00118 (179/152252) while in subpopulation EAS AF= 0.0267 (138/5172). AF 95% confidence interval is 0.0231. There are 4 homozygotes in gnomad4. There are 102 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDK5	NM_004935.4	c.*5C>T		3_prime_UTR_variant	12/12	ENST00000485972.6
CDK5	NM_001164410.3	c.*5C>T		3_prime_UTR_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDK5	ENST00000485972.6	c.*5C>T		3_prime_UTR_variant	12/12	1	NM_004935.4	P1
CDK5	ENST00000297518.4			downstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 180 AN: 152134 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.0266

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00256 AC: 504 AN: 197196 Hom.: 14 AF XY: 0.00265 AC XY: 282 AN XY: 106486

Gnomad AFR exome AF: 0.0000892

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00672

Gnomad EAS exome AF: 0.0291

Gnomad SAS exome AF: 0.000156

Gnomad FIN exome AF: 0.0000586

Gnomad NFE exome AF: 0.0000818

Gnomad OTH exome AF: 0.000974

GnomAD4 exome AF: 0.000793 AC: 1135 AN: 1430440 Hom.: 19 Cov.: 32 AF XY: 0.000821 AC XY: 582 AN XY: 708508

Gnomad4 AFR exome AF: 0.0000304

Gnomad4 AMR exome AF: 0.0000505

Gnomad4 ASJ exome AF: 0.00575

Gnomad4 EAS exome AF: 0.0218

Gnomad4 SAS exome AF: 0.000269

Gnomad4 FIN exome AF: 0.0000589

Gnomad4 NFE exome AF: 0.0000456

Gnomad4 OTH exome AF: 0.00123

GnomAD4 genome AF: 0.00118 AC: 179 AN: 152252 Hom.: 4 Cov.: 32 AF XY: 0.00137 AC XY: 102 AN XY: 74448

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00778

Gnomad4 EAS AF: 0.0267

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000535 Hom.: 0

Bravo AF: 0.00155

Asia WGS AF: 0.00664 AC: 23 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

CDK5-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 28, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	6.2
Dann	Benign	0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs2069460; hg19: chr7-150751091;