rs606231255

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PM5PP2

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

2
6
11

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.90
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 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.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CDK6. . Gene score misZ 3.0596 (greater than the threshold 3.09). Trascript score misZ 3.1324 (greater than threshold 3.09). GenCC has associacion of gene with autosomal recessive primary microcephaly, microcephaly 12, primary, autosomal recessive.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CDK6NM_001145306.2 linkuse as main transcriptc.589G>T p.Ala197Ser missense_variant 5/8 ENST00000424848.3
CDK6NM_001259.8 linkuse as main transcriptc.589G>T p.Ala197Ser missense_variant 5/8
CDK6XM_047419716.1 linkuse as main transcriptc.589G>T p.Ala197Ser missense_variant 5/8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CDK6ENST00000424848.3 linkuse as main transcriptc.589G>T p.Ala197Ser missense_variant 5/81 NM_001145306.2 P1
CDK6ENST00000265734.8 linkuse as main transcriptc.589G>T p.Ala197Ser missense_variant 5/81 P1
CDK6ENST00000473078.1 linkuse as main transcriptn.137G>T non_coding_transcript_exon_variant 2/22

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1429148
Hom.:
0
Cov.:
29
AF XY:
0.00
AC XY:
0
AN XY:
710998
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

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
T
BayesDel_noAF
Benign
-0.24
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Benign
0.35
T;T
Eigen
Benign
0.13
Eigen_PC
Uncertain
0.29
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.97
.;D
M_CAP
Uncertain
0.21
D
MetaRNN
Uncertain
0.62
D;D
MetaSVM
Benign
-0.89
T
MutationAssessor
Benign
-0.54
N;N
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.81
D
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
D
GERP RS
5.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.1
Varity_R
0.75
gMVP
0.61

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-92300798; API