7-92630946-T-C

Variant names:

• chr7-92630946-T-C
• rs2237572
• NM_001145306.2:c.648-7860A>G

Variant summary

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

The NM_001145306.2(CDK6):​c.648-7860A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.29 in 152,048 control chromosomes in the GnomAD database, including 7,888 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 0.29 (7888 hom., cov: 32)
• Consequence: CDK6 NM_001145306.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0920
• Publications: 11 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=-0.73).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.775 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.648-7860A>G		intron	N/A	NP_001138778.1	Q00534
	CDK6	NM_001259.8		c.648-7860A>G		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.648-7860A>G		intron	N/A	ENSP00000397087.3	Q00534
	CDK6	ENST00000265734.8	TSL:1	c.648-7860A>G		intron	N/A	ENSP00000265734.4	Q00534
	CDK6	ENST00000906280.1		c.648-7860A>G		intron	N/A	ENSP00000576339.1

Frequencies

GnomAD3 genomes AF: 0.290 AC: 44078 AN: 151930 Hom.: 7875 Cov.: 32

Gnomad AFR AF: 0.360

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.460

Gnomad ASJ AF: 0.142

Gnomad EAS AF: 0.796

Gnomad SAS AF: 0.271

Gnomad FIN AF: 0.219

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.194

Gnomad OTH AF: 0.284

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

GnomAD4 genome AF: 0.290 AC: 44142 AN: 152048 Hom.: 7888 Cov.: 32 AF XY: 0.297 AC XY: 22076 AN XY: 74340

African (AFR) AF: 0.360 AC: 14925 AN: 41456

American (AMR) AF: 0.461 AC: 7034 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 494 AN: 3470

East Asian (EAS) AF: 0.795 AC: 4110 AN: 5168

South Asian (SAS) AF: 0.271 AC: 1306 AN: 4826

European-Finnish (FIN) AF: 0.219 AC: 2321 AN: 10582

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.194 AC: 13209 AN: 67976

Other (OTH) AF: 0.285 AC: 601 AN: 2110

Alfa AF: 0.234 Hom.: 3491

Bravo AF: 0.314

Asia WGS AF: 0.508 AC: 1760 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	12
DANN	Benign	0.76
PhyloP100		0.092
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: rs2237572; hg19: chr7-92260260;