chr7-92622889-C-A

Variant names:

• chr7-92622889-C-A
• rs42046
• NM_001145306.2:c.698+147G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001145306.2(CDK6):​c.698+147G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000226 in 442,544 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 31)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: CDK6 NM_001145306.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.68
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.23).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK6	NM_001145306.2	c.698+147G>T		intron_variant	Intron 6 of 7	ENST00000424848.3	NP_001138778.1
CDK6	NM_001259.8	c.698+147G>T		intron_variant	Intron 6 of 7		NP_001250.1
CDK6	XM_047419716.1	c.698+147G>T		intron_variant	Intron 6 of 7		XP_047275672.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK6	ENST00000424848.3	c.698+147G>T		intron_variant	Intron 6 of 7	1	NM_001145306.2	ENSP00000397087.3
CDK6	ENST00000265734.8	c.698+147G>T		intron_variant	Intron 6 of 7	1		ENSP00000265734.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000226 AC: 1 AN: 442544 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 232908

African (AFR) AF: 0.00 AC: 0 AN: 12164

American (AMR) AF: 0.00 AC: 0 AN: 18672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12984

East Asian (EAS) AF: 0.00 AC: 0 AN: 30278

South Asian (SAS) AF: 0.00 AC: 0 AN: 40324

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42080

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3180

European-Non Finnish (NFE) AF: 0.00000387 AC: 1 AN: 258150

Other (OTH) AF: 0.00 AC: 0 AN: 24712

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
CADD	Benign	20
DANN	Benign	0.79
PhyloP100		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs42046; hg19: chr7-92252203;