rs17690388

Variant names:

• chr7-92716043-G-A
• rs17690388
• NM_001145306.2:c.537+9583C>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.537+9583C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0305 in 152,288 control chromosomes in the GnomAD database, including 99 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 0.031 (99 hom., cov: 32)
• Consequence: CDK6 NM_001145306.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.777
• Publications: 4 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=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0527 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK6	NM_001145306.2	c.537+9583C>T		intron_variant	Intron 4 of 7	ENST00000424848.3	NP_001138778.1
CDK6	NM_001259.8	c.537+9583C>T		intron_variant	Intron 4 of 7		NP_001250.1
CDK6	XM_047419716.1	c.537+9583C>T		intron_variant	Intron 4 of 7		XP_047275672.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK6	ENST00000424848.3	c.537+9583C>T		intron_variant	Intron 4 of 7	1	NM_001145306.2	ENSP00000397087.3
CDK6	ENST00000265734.8	c.537+9583C>T		intron_variant	Intron 4 of 7	1		ENSP00000265734.4
CDK6	ENST00000473078.1	n.85+9583C>T		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes AF: 0.0305 AC: 4647 AN: 152170 Hom.: 99 Cov.: 32

Gnomad AFR AF: 0.00852

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.00884

Gnomad ASJ AF: 0.0254

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0106

Gnomad FIN AF: 0.0274

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0541

Gnomad OTH AF: 0.0191

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

GnomAD4 genome AF: 0.0305 AC: 4646 AN: 152288 Hom.: 99 Cov.: 32 AF XY: 0.0281 AC XY: 2093 AN XY: 74464

African (AFR) AF: 0.00849 AC: 353 AN: 41574

American (AMR) AF: 0.00876 AC: 134 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0254 AC: 88 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.0106 AC: 51 AN: 4826

European-Finnish (FIN) AF: 0.0274 AC: 291 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0541 AC: 3682 AN: 68012

Other (OTH) AF: 0.0185 AC: 39 AN: 2112

Alfa AF: 0.0462 Hom.: 291

Bravo AF: 0.0279

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	13
DANN	Benign	0.61
PhyloP100		0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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: rs17690388; hg19: chr7-92345357;