rs2374589

Variant names:

• chr7-92816166-A-G
• rs2374589
• NM_001145306.2:c.233+16925T>C

Variant summary

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

The NM_001145306.2(CDK6):​c.233+16925T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 152,190 control chromosomes in the GnomAD database, including 2,336 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 (2336 hom., cov: 32)
• Consequence: CDK6 NM_001145306.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.247
• Publications: 9 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.294 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.233+16925T>C		intron	N/A	NP_001138778.1	Q00534
	CDK6	NM_001259.8		c.233+16925T>C		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.233+16925T>C		intron	N/A	ENSP00000397087.3	Q00534
	CDK6	ENST00000265734.8	TSL:1	c.233+16925T>C		intron	N/A	ENSP00000265734.4	Q00534
	CDK6	ENST00000906280.1		c.233+16925T>C		intron	N/A	ENSP00000576339.1

Frequencies

GnomAD3 genomes AF: 0.137 AC: 20829 AN: 152072 Hom.: 2316 Cov.: 32

Gnomad AFR AF: 0.298

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.0888

Gnomad ASJ AF: 0.0441

Gnomad EAS AF: 0.0814

Gnomad SAS AF: 0.263

Gnomad FIN AF: 0.0442

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0668

Gnomad OTH AF: 0.125

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

GnomAD4 genome AF: 0.137 AC: 20896 AN: 152190 Hom.: 2336 Cov.: 32 AF XY: 0.138 AC XY: 10294 AN XY: 74432

African (AFR) AF: 0.298 AC: 12375 AN: 41498

American (AMR) AF: 0.0885 AC: 1353 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0441 AC: 153 AN: 3470

East Asian (EAS) AF: 0.0820 AC: 425 AN: 5184

South Asian (SAS) AF: 0.261 AC: 1258 AN: 4820

European-Finnish (FIN) AF: 0.0442 AC: 469 AN: 10612

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0668 AC: 4542 AN: 68006

Other (OTH) AF: 0.130 AC: 274 AN: 2114

Alfa AF: 0.0963 Hom.: 2349

Bravo AF: 0.142

Asia WGS AF: 0.234 AC: 814 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.5
DANN	Benign	0.48
PhyloP100		-0.25
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs2374589; hg19: chr7-92445480;