rs2374594

Variant names:

• chr7-92767977-G-A
• rs2374594
• NM_001145306.2:c.369+6719C>T

Variant summary

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

The NM_001145306.2(CDK6):​c.369+6719C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0586 in 151,932 control chromosomes in the GnomAD database, including 331 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 0.059 (331 hom., cov: 32)
• Consequence: CDK6 NM_001145306.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.428
• 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=-0.87).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0983 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDK6	NM_001145306.2	MANE Select	c.369+6719C>T		intron	N/A	NP_001138778.1
	CDK6	NM_001259.8		c.369+6719C>T		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.369+6719C>T		intron	N/A	ENSP00000397087.3
	CDK6	ENST00000265734.8	TSL:1	c.369+6719C>T		intron	N/A	ENSP00000265734.4

Frequencies

GnomAD3 genomes AF: 0.0586 AC: 8899 AN: 151814 Hom.: 333 Cov.: 32

Gnomad AFR AF: 0.0197

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0531

Gnomad ASJ AF: 0.0378

Gnomad EAS AF: 0.0330

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.0752

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0807

Gnomad OTH AF: 0.0699

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

GnomAD4 genome AF: 0.0586 AC: 8896 AN: 151932 Hom.: 331 Cov.: 32 AF XY: 0.0586 AC XY: 4350 AN XY: 74252

African (AFR) AF: 0.0197 AC: 817 AN: 41414

American (AMR) AF: 0.0530 AC: 808 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.0378 AC: 131 AN: 3468

East Asian (EAS) AF: 0.0330 AC: 171 AN: 5174

South Asian (SAS) AF: 0.106 AC: 510 AN: 4814

European-Finnish (FIN) AF: 0.0752 AC: 793 AN: 10548

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0807 AC: 5487 AN: 67952

Other (OTH) AF: 0.0706 AC: 149 AN: 2110

Alfa AF: 0.0725 Hom.: 259

Bravo AF: 0.0535

Asia WGS AF: 0.100 AC: 347 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.4
DANN	Benign	0.61
PhyloP100		0.43
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: rs2374594; hg19: chr7-92397291;