rs902137115

Variant names:

• chr7-92618206-C-G
• rs902137115
• NM_001145306.2:c.700G>C

Your query was ambiguous. Multiple possible variants found:

• chr7-92618206-C-G
• chr7-92618206-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001145306.2(CDK6):​c.700G>C​(p.Val234Leu) variant causes a missense, splice region 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. 17/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. V234M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDK6 NM_001145306.2 missense, splice_region
• Scores: Splicing: ADA: 0.0003000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.64
• Publications: 0 publications found

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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12762362).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK6	NM_001145306.2	c.700G>C	p.Val234Leu	missense_variant, splice_region_variant	Exon 7 of 8	ENST00000424848.3	NP_001138778.1
CDK6	NM_001259.8	c.700G>C	p.Val234Leu	missense_variant, splice_region_variant	Exon 7 of 8		NP_001250.1
CDK6	XM_047419716.1	c.700G>C	p.Val234Leu	missense_variant, splice_region_variant	Exon 7 of 8		XP_047275672.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK6	ENST00000424848.3	c.700G>C	p.Val234Leu	missense_variant, splice_region_variant	Exon 7 of 8	1	NM_001145306.2	ENSP00000397087.3
CDK6	ENST00000265734.8	c.700G>C	p.Val234Leu	missense_variant, splice_region_variant	Exon 7 of 8	1		ENSP00000265734.4
CDK6	ENST00000467166.1	n.72G>C		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	16
DANN	Benign	0.56
DEOGEN2	Benign	0.31	T;T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.45
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.44	.;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.23	N;N
PhyloP100		1.6
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.96	N;N
REVEL	Benign	0.22
Sift	Benign	0.81	T;T
Sift4G	Benign	0.64	T;T
Polyphen		0.013	B;B
Vest4		0.39
MutPred		0.41		Gain of ubiquitination at K230 (P = 0.0797);Gain of ubiquitination at K230 (P = 0.0797);
MVP		0.72
MPC		1.2
ClinPred		0.12	T
GERP RS		4.0
Varity_R		0.19
gMVP		0.79
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00030
dbscSNV1_RF	Benign	0.012
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

Other links and lift over

dbSNP: rs902137115; hg19: chr7-92247520;