chr7-92615172-T-C

Position:

• chr7-92615172-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001145306.2(CDK6):​c.949A>G​(p.Ser317Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDK6 NM_001145306.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.24

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]

CDK6 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.12454137).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDK6	NM_001145306.2	c.949A>G	p.Ser317Gly	missense_variant	8/8	ENST00000424848.3	NP_001138778.1
CDK6	NM_001259.8	c.949A>G	p.Ser317Gly	missense_variant	8/8		NP_001250.1
CDK6	XM_047419716.1	c.949A>G	p.Ser317Gly	missense_variant	8/8		XP_047275672.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDK6	ENST00000424848.3	c.949A>G	p.Ser317Gly	missense_variant	8/8	1	NM_001145306.2	ENSP00000397087.3
CDK6	ENST00000265734.8	c.949A>G	p.Ser317Gly	missense_variant	8/8	1		ENSP00000265734.4
CDK6	ENST00000467166.1	n.321A>G		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	18
DANN	Benign	0.84
DEOGEN2	Benign	0.38	T;T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.61
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.60	.;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.90	L;L
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.49	N;N
REVEL	Benign	0.13
Sift	Benign	0.17	T;T
Sift4G	Benign	0.60	T;T
Polyphen		0.0	B;B
Vest4		0.11
MutPred		0.18		Loss of glycosylation at P315 (P = 0.076);Loss of glycosylation at P315 (P = 0.076);
MVP		0.60
MPC		1.1
ClinPred		0.060	T
GERP RS		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.054
gMVP		0.28

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

Publications

LitVar

Other links and lift over

dbSNP: rs140409009; hg19: chr7-92244486;