7-92644222-A-C

Variant names:

• chr7-92644222-A-C
• rs3731343
• NM_001145306.2:c.648-21136T>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.648-21136T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.643 in 152,058 control chromosomes in the GnomAD database, including 32,835 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 0.64 (32835 hom., cov: 31)
• Consequence: CDK6 NM_001145306.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.408
• Publications: 14 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.816 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.648-21136T>G		intron	N/A	NP_001138778.1
	CDK6	NM_001259.8		c.648-21136T>G		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.648-21136T>G		intron	N/A	ENSP00000397087.3
	CDK6	ENST00000265734.8	TSL:1	c.648-21136T>G		intron	N/A	ENSP00000265734.4
	ENSG00000286742	ENST00000720891.1		n.307+78A>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.643 AC: 97632 AN: 151940 Hom.: 32782 Cov.: 31

Gnomad AFR AF: 0.823

Gnomad AMI AF: 0.459

Gnomad AMR AF: 0.740

Gnomad ASJ AF: 0.578

Gnomad EAS AF: 0.817

Gnomad SAS AF: 0.444

Gnomad FIN AF: 0.511

Gnomad MID AF: 0.601

Gnomad NFE AF: 0.538

Gnomad OTH AF: 0.642

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

GnomAD4 genome AF: 0.643 AC: 97743 AN: 152058 Hom.: 32835 Cov.: 31 AF XY: 0.643 AC XY: 47768 AN XY: 74310

African (AFR) AF: 0.823 AC: 34174 AN: 41506

American (AMR) AF: 0.741 AC: 11323 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.578 AC: 2005 AN: 3470

East Asian (EAS) AF: 0.816 AC: 4226 AN: 5180

South Asian (SAS) AF: 0.445 AC: 2144 AN: 4818

European-Finnish (FIN) AF: 0.511 AC: 5388 AN: 10546

Middle Eastern (MID) AF: 0.599 AC: 176 AN: 294

European-Non Finnish (NFE) AF: 0.538 AC: 36542 AN: 67936

Other (OTH) AF: 0.639 AC: 1347 AN: 2108

Alfa AF: 0.574 Hom.: 42624

Bravo AF: 0.672

Asia WGS AF: 0.650 AC: 2260 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.3
DANN	Benign	0.43
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: rs3731343; hg19: chr7-92273536;