dbSNP rs606231255: CDK6:p.Ala197Ser (chr7-92671484-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PM5

The NM_001145306.2(CDK6):c.589G>T(p.Ala197Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A197T) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CDK6
NM_001145306.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.90

Publications

0 publications found

Variant links:

Genes affected

CDK6 (HGNC:1777): (cyclin dependent kinase 6) The protein encoded by this gene is a member of the CMGC family of serine/threonine protein kinases. This kinase is a catalytic subunit of the protein kinase complex that is important for cell cycle G1 phase progression and G1/S transition. The activity of this kinase first appears in mid-G1 phase, which is controlled by the regulatory subunits including D-type cyclins and members of INK4 family of CDK inhibitors. This kinase, as well as CDK4, has been shown to phosphorylate, and thus regulate the activity of, tumor suppressor protein Rb. Altered expression of this gene has been observed in multiple human cancers. A mutation in this gene resulting in reduced cell proliferation, and impaired cell motility and polarity, and has been identified in patients with primary microcephaly. [provided by RefSeq, Aug 2017]

CDK6 Gene-Disease associations (from GenCC):

autosomal recessive primary microcephaly
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
microcephaly 12, primary, autosomal recessive
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

CDK6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-92671484-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 157508.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK6	NM_001145306.2 link	c.589G>T	p.Ala197Ser	missense_variant	Exon 5 of 8	ENST00000424848.3	NP_001138778.1	Q00534
CDK6	NM_001259.8 link	c.589G>T	p.Ala197Ser	missense_variant	Exon 5 of 8		NP_001250.1	Q00534
CDK6	XM_047419716.1 link	c.589G>T	p.Ala197Ser	missense_variant	Exon 5 of 8		XP_047275672.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CDK6	ENST00000424848.3 link	c.589G>T	p.Ala197Ser	missense_variant	Exon 5 of 8	1	NM_001145306.2	ENSP00000397087.3	Q00534
CDK6	ENST00000265734.8 link	c.589G>T	p.Ala197Ser	missense_variant	Exon 5 of 8	1		ENSP00000265734.4	Q00534
CDK6	ENST00000473078.1 link	n.137G>T		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1429148

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

710998

African (AFR)

AF:

0.00

AC:

AN:

31526

American (AMR)

AF:

0.00

AC:

AN:

40696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25334

East Asian (EAS)

AF:

0.00

AC:

AN:

36530

South Asian (SAS)

AF:

0.00

AC:

AN:

82080

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52740

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5622

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1095702

Other (OTH)

AF:

0.00

AC:

AN:

58918

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.00051

BayesDel_noAF

Benign

-0.24

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

T;T

Eigen

Benign

0.13

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

.;D

M_CAP

Uncertain

0.21

MetaRNN

Uncertain

0.62

D;D

MetaSVM

Benign

-0.89

MutationAssessor

Benign

-0.54

N;N

PhyloP100

7.9

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-1.7

N;N

REVEL

Uncertain

0.43

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

1.0

D;D

Vest4

0.59

MutPred

0.53

Gain of glycosylation at A197 (P = 0.0477);Gain of glycosylation at A197 (P = 0.0477);

MVP

0.69

MPC

1.1

ClinPred

0.97

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.75

gMVP

0.61

Mutation Taster

=49/51

disease causing

(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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over