rs2282979

Variant names:

• chr7-92635679-T-C
• rs2282979
• NM_001145306.2:c.648-12593A>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.648-12593A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.24 in 152,154 control chromosomes in the GnomAD database, including 4,793 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 0.24 (4793 hom., cov: 32)
• Consequence: CDK6 NM_001145306.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.211
• Publications: 10 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=-0.83).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.329 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK6	NM_001145306.2	c.648-12593A>G		intron_variant	Intron 5 of 7	ENST00000424848.3	NP_001138778.1
CDK6	NM_001259.8	c.648-12593A>G		intron_variant	Intron 5 of 7		NP_001250.1
CDK6	XM_047419716.1	c.648-12593A>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.648-12593A>G		intron_variant	Intron 5 of 7	1	NM_001145306.2	ENSP00000397087.3
CDK6	ENST00000265734.8	c.648-12593A>G		intron_variant	Intron 5 of 7	1		ENSP00000265734.4

Frequencies

GnomAD3 genomes AF: 0.240 AC: 36445 AN: 152036 Hom.: 4799 Cov.: 32

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.328

Gnomad AMR AF: 0.337

Gnomad ASJ AF: 0.344

Gnomad EAS AF: 0.109

Gnomad SAS AF: 0.144

Gnomad FIN AF: 0.250

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.283

Gnomad OTH AF: 0.279

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

GnomAD4 genome AF: 0.240 AC: 36449 AN: 152154 Hom.: 4793 Cov.: 32 AF XY: 0.239 AC XY: 17807 AN XY: 74370

African (AFR) AF: 0.145 AC: 6006 AN: 41524

American (AMR) AF: 0.337 AC: 5138 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.344 AC: 1192 AN: 3466

East Asian (EAS) AF: 0.110 AC: 569 AN: 5182

South Asian (SAS) AF: 0.144 AC: 696 AN: 4822

European-Finnish (FIN) AF: 0.250 AC: 2643 AN: 10570

Middle Eastern (MID) AF: 0.374 AC: 110 AN: 294

European-Non Finnish (NFE) AF: 0.283 AC: 19213 AN: 68002

Other (OTH) AF: 0.276 AC: 583 AN: 2114

Alfa AF: 0.271 Hom.: 16174

Bravo AF: 0.246

Asia WGS AF: 0.151 AC: 528 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.6
DANN	Benign	0.65
PhyloP100		-0.21
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: rs2282979; hg19: chr7-92264993;