chr7-92805872-C-T

Variant names:

• chr7-92805872-C-T
• rs6975474
• NM_001145306.2:c.233+27219G>A

Variant summary

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

The NM_001259.8(CDK6):​c.233+27219G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 152,022 control chromosomes in the GnomAD database, including 2,972 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 0.15 (2972 hom., cov: 32)
• Consequence: CDK6 NM_001259.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.415
• Publications: 8 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=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.345 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001259.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDK6	NM_001145306.2	MANE Select	c.233+27219G>A		intron	N/A	NP_001138778.1
	CDK6	NM_001259.8		c.233+27219G>A		intron	N/A	NP_001250.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDK6	ENST00000424848.3	TSL:1 MANE Select	c.233+27219G>A		intron	N/A	ENSP00000397087.3
	CDK6	ENST00000265734.8	TSL:1	c.233+27219G>A		intron	N/A	ENSP00000265734.4
	CDK6	ENST00000906280.1		c.233+27219G>A		intron	N/A	ENSP00000576339.1

Frequencies

GnomAD3 genomes AF: 0.151 AC: 22967 AN: 151904 Hom.: 2944 Cov.: 32

Gnomad AFR AF: 0.348

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.0914

Gnomad ASJ AF: 0.0441

Gnomad EAS AF: 0.0809

Gnomad SAS AF: 0.264

Gnomad FIN AF: 0.0442

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0668

Gnomad OTH AF: 0.133

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

GnomAD4 genome AF: 0.152 AC: 23051 AN: 152022 Hom.: 2972 Cov.: 32 AF XY: 0.152 AC XY: 11307 AN XY: 74318

African (AFR) AF: 0.349 AC: 14474 AN: 41424

American (AMR) AF: 0.0911 AC: 1390 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.0441 AC: 153 AN: 3472

East Asian (EAS) AF: 0.0814 AC: 422 AN: 5182

South Asian (SAS) AF: 0.263 AC: 1265 AN: 4818

European-Finnish (FIN) AF: 0.0442 AC: 468 AN: 10580

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0668 AC: 4540 AN: 67976

Other (OTH) AF: 0.137 AC: 289 AN: 2106

Alfa AF: 0.0910 Hom.: 4259

Bravo AF: 0.158

Asia WGS AF: 0.238 AC: 827 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	4.9
DANN	Benign	0.35
PhyloP100		0.41
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: rs6975474; hg19: chr7-92435186;