NM_001145306.2:c.234-4225G>A

Variant names:

• chr7-92779056-C-T
• rs445
• NM_001145306.2:c.234-4225G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001145306.2(CDK6):​c.234-4225G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 151,666 control chromosomes in the GnomAD database, including 1,867 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.14 (1867 hom., cov: 31)
• Consequence: CDK6 NM_001145306.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.684
• Publications: 61 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.332 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145306.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDK6	NM_001145306.2	MANE Select	c.234-4225G>A		intron	N/A	NP_001138778.1	Q00534
	CDK6	NM_001259.8		c.234-4225G>A		intron	N/A	NP_001250.1	Q00534

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDK6	ENST00000424848.3	TSL:1 MANE Select	c.234-4225G>A		intron	N/A	ENSP00000397087.3	Q00534
	CDK6	ENST00000265734.8	TSL:1	c.234-4225G>A		intron	N/A	ENSP00000265734.4	Q00534
	CDK6	ENST00000906280.1		c.234-4225G>A		intron	N/A	ENSP00000576339.1

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21627 AN: 151552 Hom.: 1869 Cov.: 31

Gnomad AFR AF: 0.189

Gnomad AMI AF: 0.0934

Gnomad AMR AF: 0.161

Gnomad ASJ AF: 0.209

Gnomad EAS AF: 0.345

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.0559

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.172

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.143 AC: 21651 AN: 151666 Hom.: 1867 Cov.: 31 AF XY: 0.141 AC XY: 10462 AN XY: 74114

African (AFR) AF: 0.189 AC: 7805 AN: 41268

American (AMR) AF: 0.161 AC: 2459 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.209 AC: 724 AN: 3464

East Asian (EAS) AF: 0.345 AC: 1778 AN: 5154

South Asian (SAS) AF: 0.126 AC: 603 AN: 4786

European-Finnish (FIN) AF: 0.0559 AC: 588 AN: 10516

Middle Eastern (MID) AF: 0.310 AC: 91 AN: 294

European-Non Finnish (NFE) AF: 0.105 AC: 7158 AN: 67940

Other (OTH) AF: 0.171 AC: 360 AN: 2104

Alfa AF: 0.127 Hom.: 6484

Bravo AF: 0.157

Asia WGS AF: 0.203 AC: 705 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.3
DANN	Benign	0.69
PhyloP100		-0.68
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs445; hg19: chr7-92408370;