rs2069459

Positions:

• chr7-151054503-C-A
• chr7-151054503-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004935.4(CDK5):​c.651-38G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.368 in 1,584,148 control chromosomes in the GnomAD database, including 108,437 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.38 (11364 hom., cov: 31)
  • Exomes 𝑓: 0.37 (97073 hom.)
• Consequence: CDK5 NM_004935.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.273

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.414 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDK5	NM_004935.4	c.651-38G>T		intron_variant		ENST00000485972.6	NP_004926.1
CDK5	NM_001164410.3	c.555-38G>T		intron_variant			NP_001157882.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDK5	ENST00000485972.6	c.651-38G>T		intron_variant		1	NM_004935.4	ENSP00000419782.1
CDK5	ENST00000297518.4	c.555-38G>T		intron_variant		1		ENSP00000297518.4

Frequencies

GnomAD3 genomes AF: 0.383 AC: 58120 AN: 151724 Hom.: 11362 Cov.: 31

Gnomad AFR AF: 0.420

Gnomad AMI AF: 0.291

Gnomad AMR AF: 0.329

Gnomad ASJ AF: 0.410

Gnomad EAS AF: 0.360

Gnomad SAS AF: 0.339

Gnomad FIN AF: 0.433

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.370

Gnomad OTH AF: 0.386

GnomAD3 exomes AF: 0.355 AC: 82337 AN: 232218 Hom.: 14987 AF XY: 0.358 AC XY: 44860 AN XY: 125150

Gnomad AFR exome AF: 0.426

Gnomad AMR exome AF: 0.221

Gnomad ASJ exome AF: 0.422

Gnomad EAS exome AF: 0.355

Gnomad SAS exome AF: 0.344

Gnomad FIN exome AF: 0.431

Gnomad NFE exome AF: 0.367

Gnomad OTH exome AF: 0.371

GnomAD4 exome AF: 0.366 AC: 524158 AN: 1432306 Hom.: 97073 Cov.: 28 AF XY: 0.366 AC XY: 259782 AN XY: 710318

Gnomad4 AFR exome AF: 0.423

Gnomad4 AMR exome AF: 0.228

Gnomad4 ASJ exome AF: 0.416

Gnomad4 EAS exome AF: 0.374

Gnomad4 SAS exome AF: 0.345

Gnomad4 FIN exome AF: 0.424

Gnomad4 NFE exome AF: 0.367

Gnomad4 OTH exome AF: 0.377

GnomAD4 genome AF: 0.383 AC: 58160 AN: 151842 Hom.: 11364 Cov.: 31 AF XY: 0.385 AC XY: 28535 AN XY: 74206

Gnomad4 AFR AF: 0.419

Gnomad4 AMR AF: 0.329

Gnomad4 ASJ AF: 0.410

Gnomad4 EAS AF: 0.361

Gnomad4 SAS AF: 0.341

Gnomad4 FIN AF: 0.433

Gnomad4 NFE AF: 0.370

Gnomad4 OTH AF: 0.386

Alfa AF: 0.371 Hom.: 22211

Bravo AF: 0.375

Asia WGS AF: 0.338 AC: 1175 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.4
DANN	Benign	0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs2069459; hg19: chr7-150751590; COSMIC: COSV52520297; COSMIC: COSV52520297;