7-92615211-C-G

Position:

• chr7-92615211-C-G

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.910G>C​(p.Glu304Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDK6 NM_001145306.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.53

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 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=0.16680402).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDK6	NM_001145306.2	c.910G>C	p.Glu304Gln	missense_variant	8/8	ENST00000424848.3
CDK6	NM_001259.8	c.910G>C	p.Glu304Gln	missense_variant	8/8
CDK6	XM_047419716.1	c.910G>C	p.Glu304Gln	missense_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDK6	ENST00000424848.3	c.910G>C	p.Glu304Gln	missense_variant	8/8	1	NM_001145306.2	P1
CDK6	ENST00000265734.8	c.910G>C	p.Glu304Gln	missense_variant	8/8	1		P1
CDK6	ENST00000467166.1	n.282G>C		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 12, 2024

The c.910G>C (p.E304Q) alteration is located in exon 8 (coding exon 7) of the CDK6 gene. This alteration results from a G to C substitution at nucleotide position 910, causing the glutamic acid (E) at amino acid position 304 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T;T
Eigen	Benign	-0.066
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.77	.;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.34	N;N
MutationTaster	Benign	0.98	D;D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.29	N;N
REVEL	Benign	0.12
Sift	Benign	0.17	T;T
Sift4G	Benign	0.36	T;T
Polyphen		0.0040	B;B
Vest4		0.14
MutPred		0.31		Loss of ubiquitination at K307 (P = 0.0937);Loss of ubiquitination at K307 (P = 0.0937);
MVP		0.59
MPC		1.1
ClinPred		0.44	T
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.55
gMVP		0.32

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: rs1029909801; hg19: chr7-92244525;