chr7-92623075-C-G

Variant names:

• chr7-92623075-C-G
• rs369229292
• NM_001145306.2:c.659G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001145306.2(CDK6):​c.659G>C​(p.Arg220Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000699 in 1,430,074 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: CDK6 NM_001145306.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.24

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK6	NM_001145306.2	c.659G>C	p.Arg220Pro	missense_variant	Exon 6 of 8	ENST00000424848.3	NP_001138778.1
CDK6	NM_001259.8	c.659G>C	p.Arg220Pro	missense_variant	Exon 6 of 8		NP_001250.1
CDK6	XM_047419716.1	c.659G>C	p.Arg220Pro	missense_variant	Exon 6 of 8		XP_047275672.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK6	ENST00000424848.3	c.659G>C	p.Arg220Pro	missense_variant	Exon 6 of 8	1	NM_001145306.2	ENSP00000397087.3
CDK6	ENST00000265734.8	c.659G>C	p.Arg220Pro	missense_variant	Exon 6 of 8	1		ENSP00000265734.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000857 AC: 2 AN: 233276 Hom.: 0 AF XY: 0.0000159 AC XY: 2 AN XY: 126090

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000694

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.99e-7 AC: 1 AN: 1430074 Hom.: 0 Cov.: 25 AF XY: 0.00000140 AC XY: 1 AN XY: 712050

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: 0.0000119

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	Uncertain	0.47
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	25
DANN	Benign	0.64
DEOGEN2	Benign	0.26	T;T
Eigen	Benign	-0.10
Eigen_PC	Benign	0.12
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	.;D
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.64	D;D
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.53	N;N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	1.3	N;N
REVEL	Uncertain	0.30
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.54	P;P
Vest4		0.75
MutPred		0.61		Loss of catalytic residue at R220 (P = 0.0137);Loss of catalytic residue at R220 (P = 0.0137);
MVP		0.93
MPC		2.5
ClinPred		0.91	D
GERP RS		5.2
Varity_R		0.82
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs369229292; hg19: chr7-92252389;