rs11765954

Variant names:

• chr7-92651381-T-C
• rs11765954
• NM_001145306.2:c.647+20045A>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.647+20045A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.221 in 152,150 control chromosomes in the GnomAD database, including 4,203 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 0.22 (4203 hom., cov: 32)
• Consequence: CDK6 NM_001145306.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0970
• Publications: 15 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)

LOC112268009 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.279 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK6	NM_001145306.2	c.647+20045A>G		intron_variant	Intron 5 of 7	ENST00000424848.3	NP_001138778.1
LOC112268009	XR_002956577.2	n.11290A>G		non_coding_transcript_exon_variant	Exon 1 of 2
CDK6	NM_001259.8	c.647+20045A>G		intron_variant	Intron 5 of 7		NP_001250.1
CDK6	XM_047419716.1	c.647+20045A>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.647+20045A>G		intron_variant	Intron 5 of 7	1	NM_001145306.2	ENSP00000397087.3
CDK6	ENST00000265734.8	c.647+20045A>G		intron_variant	Intron 5 of 7	1		ENSP00000265734.4
ENSG00000286742	ENST00000668236.1	n.114-2018T>C		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes AF: 0.222 AC: 33694 AN: 152032 Hom.: 4212 Cov.: 32

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.328

Gnomad AMR AF: 0.213

Gnomad ASJ AF: 0.346

Gnomad EAS AF: 0.0231

Gnomad SAS AF: 0.140

Gnomad FIN AF: 0.248

Gnomad MID AF: 0.379

Gnomad NFE AF: 0.283

Gnomad OTH AF: 0.263

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

GnomAD4 genome AF: 0.221 AC: 33686 AN: 152150 Hom.: 4203 Cov.: 32 AF XY: 0.219 AC XY: 16253 AN XY: 74358

African (AFR) AF: 0.136 AC: 5642 AN: 41502

American (AMR) AF: 0.213 AC: 3251 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.346 AC: 1199 AN: 3468

East Asian (EAS) AF: 0.0232 AC: 120 AN: 5182

South Asian (SAS) AF: 0.141 AC: 680 AN: 4826

European-Finnish (FIN) AF: 0.248 AC: 2622 AN: 10572

Middle Eastern (MID) AF: 0.380 AC: 111 AN: 292

European-Non Finnish (NFE) AF: 0.283 AC: 19213 AN: 68000

Other (OTH) AF: 0.260 AC: 549 AN: 2108

Alfa AF: 0.263 Hom.: 16209

Bravo AF: 0.218

Asia WGS AF: 0.0970 AC: 341 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	8.7
DANN	Benign	0.61
PhyloP100		0.097
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: rs11765954; hg19: chr7-92280695;