NM_001145306.2:c.648-12010A>G

Variant names:

• chr7-92635096-T-C
• rs2282978
• NM_001145306.2:c.648-12010A>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.648-12010A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.372 in 152,022 control chromosomes in the GnomAD database, including 11,040 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 0.37 (11040 hom., cov: 32)
• Consequence: CDK6 NM_001145306.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0340
• Publications: 70 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=-0.66).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.47 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK6	NM_001145306.2	c.648-12010A>G		intron_variant	Intron 5 of 7	ENST00000424848.3	NP_001138778.1
CDK6	NM_001259.8	c.648-12010A>G		intron_variant	Intron 5 of 7		NP_001250.1
CDK6	XM_047419716.1	c.648-12010A>G		intron_variant	Intron 5 of 7		XP_047275672.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK6	ENST00000424848.3	c.648-12010A>G		intron_variant	Intron 5 of 7	1	NM_001145306.2	ENSP00000397087.3
CDK6	ENST00000265734.8	c.648-12010A>G		intron_variant	Intron 5 of 7	1		ENSP00000265734.4

Frequencies

GnomAD3 genomes AF: 0.371 AC: 56423 AN: 151904 Hom.: 11027 Cov.: 32

Gnomad AFR AF: 0.476

Gnomad AMI AF: 0.353

Gnomad AMR AF: 0.402

Gnomad ASJ AF: 0.433

Gnomad EAS AF: 0.116

Gnomad SAS AF: 0.180

Gnomad FIN AF: 0.296

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.343

Gnomad OTH AF: 0.376

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

GnomAD4 genome AF: 0.372 AC: 56489 AN: 152022 Hom.: 11040 Cov.: 32 AF XY: 0.368 AC XY: 27331 AN XY: 74294

African (AFR) AF: 0.476 AC: 19730 AN: 41448

American (AMR) AF: 0.401 AC: 6130 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.433 AC: 1500 AN: 3464

East Asian (EAS) AF: 0.116 AC: 601 AN: 5180

South Asian (SAS) AF: 0.181 AC: 876 AN: 4828

European-Finnish (FIN) AF: 0.296 AC: 3127 AN: 10562

Middle Eastern (MID) AF: 0.442 AC: 130 AN: 294

European-Non Finnish (NFE) AF: 0.343 AC: 23287 AN: 67950

Other (OTH) AF: 0.372 AC: 786 AN: 2112

Alfa AF: 0.352 Hom.: 43690

Bravo AF: 0.387

Asia WGS AF: 0.203 AC: 709 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	18
DANN	Benign	0.71
PhyloP100		-0.034
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: rs2282978; hg19: chr7-92264410;