chr7-151054250-C-T

Position:

• chr7-151054250-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_004935.4(CDK5):​c.754G>A​(p.Val252Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,461,336 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CDK5 NM_004935.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.12

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CDK5. . Gene score misZ 3.0676 (greater than the threshold 3.09). Trascript score misZ 3.3481 (greater than threshold 3.09). GenCC has associacion of gene with lissencephaly 7 with cerebellar hypoplasia.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDK5	NM_004935.4	c.754G>A	p.Val252Met	missense_variant	11/12	ENST00000485972.6	NP_004926.1
CDK5	NM_001164410.3	c.658G>A	p.Val220Met	missense_variant	10/11		NP_001157882.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDK5	ENST00000485972.6	c.754G>A	p.Val252Met	missense_variant	11/12	1	NM_004935.4	ENSP00000419782	P1
CDK5	ENST00000297518.4	c.658G>A	p.Val220Met	missense_variant	10/11	1		ENSP00000297518

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461336 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726930

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 06, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1361450). This variant has not been reported in the literature in individuals affected with CDK5-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 252 of the CDK5 protein (p.Val252Met). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	23
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.28	T;.
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.67	D;D
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.84	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.1	N;N
REVEL	Benign	0.24
Sift	Uncertain	0.015	D;D
Sift4G	Uncertain	0.042	D;D
Polyphen		1.0	D;.
Vest4		0.75
MutPred		0.45		Gain of ubiquitination at K254 (P = 0.1096);.;
MVP		0.53
MPC		2.2
ClinPred		0.96	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.72
gMVP		0.48

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: rs1257052866; hg19: chr7-150751337;