7-151054051-C-G

Variant names:

• chr7-151054051-C-G
• rs1344288403
• NM_004935.4:c.837G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004935.4(CDK5):​c.837G>C​(p.Glu279Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,450,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E279E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CDK5 NM_004935.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0350
• Publications: 0 publications found

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]

CDK5 Gene-Disease associations (from GenCC):

• lissencephaly 7 with cerebellar hypoplasia

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• lissencephaly with cerebellar hypoplasia

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37668455).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004935.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDK5	NM_004935.4	MANE Select	c.837G>C	p.Glu279Asp	missense	Exon 12 of 12	NP_004926.1	A0A090N7W4
	CDK5	NM_001164410.3		c.741G>C	p.Glu247Asp	missense	Exon 11 of 11	NP_001157882.1	A0A0S2Z355

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDK5	ENST00000485972.6	TSL:1 MANE Select	c.837G>C	p.Glu279Asp	missense	Exon 12 of 12	ENSP00000419782.1	Q00535-1
	CDK5	ENST00000297518.4	TSL:1	c.741G>C	p.Glu247Asp	missense	Exon 11 of 11	ENSP00000297518.4	Q00535-2
	CDK5	ENST00000891064.1		c.873G>C	p.Glu291Asp	missense	Exon 12 of 12	ENSP00000561123.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1450018 Hom.: 0 Cov.: 32 AF XY: 0.00000278 AC XY: 2 AN XY: 720052

African (AFR) AF: 0.0000300 AC: 1 AN: 33328

American (AMR) AF: 0.00 AC: 0 AN: 42756

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25890

East Asian (EAS) AF: 0.00 AC: 0 AN: 39238

South Asian (SAS) AF: 0.00 AC: 0 AN: 84010

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52490

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5658

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1106632

Other (OTH) AF: 0.00 AC: 0 AN: 60016

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	15
DANN	Benign	0.90
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.61
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.68	N
PhyloP100		0.035
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.71	N
REVEL	Uncertain	0.36
Sift	Benign	0.72	T
Sift4G	Benign	0.89	T
Polyphen		0.0	B
Vest4		0.62
MutPred		0.36		Gain of helix (P = 0.132)
MVP		0.73
MPC		0.94
ClinPred		0.16	T
GERP RS		0.11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.37
gMVP		0.37
Mutation Taster		=65/35	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1344288403; hg19: chr7-150751138;