dbSNP rs2069456: CDK5:c.483+11A>C (chr7-151055521-T-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004935.4(CDK5):c.483+11A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.242 in 1,611,246 control chromosomes in the GnomAD database, including 50,996 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.25 ( 5223 hom., cov: 33)

Exomes 𝑓: 0.24 ( 45773 hom. )

Consequence

CDK5
NM_004935.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.313

Publications

26 publications found

Variant links:

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

CDK5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 7-151055521-T-G is Benign according to our data. Variant chr7-151055521-T-G is described in ClinVar as Benign. ClinVar VariationId is 1600506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.391 is higher than 0.05.

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.483+11A>C		intron	N/A	NP_004926.1	A0A090N7W4
	CDK5	NM_001164410.3		c.387+11A>C		intron	N/A	NP_001157882.1	A0A0S2Z355

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CDK5	ENST00000485972.6	TSL:1 MANE Select	c.483+11A>C	intron	N/A	ENSP00000419782.1	Q00535-1
CDK5	ENST00000297518.4	TSL:1	c.387+11A>C	intron	N/A	ENSP00000297518.4	Q00535-2
CDK5	ENST00000891064.1		c.519+11A>C	intron	N/A	ENSP00000561123.1

Frequencies

GnomAD3 genomes

AF:

0.255

AC:

38732

AN:

152054

Hom.:

5214

Cov.:

show subpopulations

Gnomad AFR

AF:

0.231

Gnomad AMI

AF:

0.265

Gnomad AMR

AF:

0.398

Gnomad ASJ

AF:

0.231

Gnomad EAS

AF:

0.332

Gnomad SAS

AF:

0.183

Gnomad FIN

AF:

0.273

Gnomad MID

AF:

0.247

Gnomad NFE

AF:

0.234

Gnomad OTH

AF:

0.261

GnomAD2 exomes

AF:

0.288

AC:

71558

AN:

248186

AF XY:

0.272

show subpopulations

Gnomad AFR exome

AF:

0.232

Gnomad AMR exome

AF:

0.574

Gnomad ASJ exome

AF:

0.222

Gnomad EAS exome

AF:

0.330

Gnomad FIN exome

AF:

0.271

Gnomad NFE exome

AF:

0.239

Gnomad OTH exome

AF:

0.278

GnomAD4 exome

AF:

0.241

AC:

351962

AN:

1459074

Hom.:

45773

Cov.:

AF XY:

0.239

AC XY:

173161

AN XY:

725948

show subpopulations

African (AFR)

AF:

0.232

AC:

7762

AN:

33436

American (AMR)

AF:

0.559

AC:

24924

AN:

44620

Ashkenazi Jewish (ASJ)

AF:

0.223

AC:

5832

AN:

26116

East Asian (EAS)

AF:

0.323

AC:

12828

AN:

39682

South Asian (SAS)

AF:

0.185

AC:

15947

AN:

86178

European-Finnish (FIN)

AF:

0.270

AC:

14382

AN:

53262

Middle Eastern (MID)

AF:

0.208

AC:

1180

AN:

5672

European-Non Finnish (NFE)

AF:

0.229

AC:

254695

AN:

1109832

Other (OTH)

AF:

0.239

AC:

14412

AN:

60276

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

13829

27658

41487

55316

69145

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8810

17620

26430

35240

44050

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.255

AC:

38755

AN:

152172

Hom.:

5223

Cov.:

AF XY:

0.258

AC XY:

19198

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.231

AC:

9575

AN:

41522

American (AMR)

AF:

0.399

AC:

6101

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.231

AC:

803

AN:

3470

East Asian (EAS)

AF:

0.331

AC:

1710

AN:

5162

South Asian (SAS)

AF:

0.182

AC:

877

AN:

4824

European-Finnish (FIN)

AF:

0.273

AC:

2900

AN:

10604

Middle Eastern (MID)

AF:

0.245

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.234

AC:

15931

AN:

67980

Other (OTH)

AF:

0.258

AC:

545

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1484

2968

4453

5937

7421

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

386

772

1158

1544

1930

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.246

Hom.:

6763

Bravo

AF:

0.272

Asia WGS

AF:

0.251

AC:

873

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

3.1

(source)

DANN

Benign

0.37

PhyloP100

-0.31

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over