rs55860121

Positions:

• chr7-92615275-T-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001145306.2(CDK6):​c.846A>G​(p.Thr282=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000686 in 1,613,478 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00072 (4 hom.)
• Consequence: CDK6 NM_001145306.2 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.623

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]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 7-92615275-T-C is Benign according to our data. Variant chr7-92615275-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 434658.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92615275-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.623 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDK6	NM_001145306.2	c.846A>G	p.Thr282=	synonymous_variant	8/8	ENST00000424848.3	NP_001138778.1
CDK6	NM_001259.8	c.846A>G	p.Thr282=	synonymous_variant	8/8		NP_001250.1
CDK6	XM_047419716.1	c.846A>G	p.Thr282=	synonymous_variant	8/8		XP_047275672.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDK6	ENST00000424848.3	c.846A>G	p.Thr282=	synonymous_variant	8/8	1	NM_001145306.2	ENSP00000397087	P1
CDK6	ENST00000265734.8	c.846A>G	p.Thr282=	synonymous_variant	8/8	1		ENSP00000265734	P1
CDK6	ENST00000467166.1	n.218A>G		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000470 AC: 117 AN: 248944 Hom.: 1 AF XY: 0.000549 AC XY: 74 AN XY: 134740

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00111

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000611

Gnomad OTH exome AF: 0.000818

GnomAD4 exome AF: 0.000717 AC: 1048 AN: 1461186 Hom.: 4 Cov.: 31 AF XY: 0.000747 AC XY: 543 AN XY: 726996

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00109

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.000776

Gnomad4 OTH exome AF: 0.000845

GnomAD4 genome AF: 0.000387 AC: 59 AN: 152292 Hom.: 0 Cov.: 32 AF XY: 0.000416 AC XY: 31 AN XY: 74458

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000691

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000457 Hom.: 0

Bravo AF: 0.000363

EpiCase AF: 0.00120

EpiControl AF: 0.000474

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 20, 2017

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	5.3
DANN	Benign	0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs55860121; hg19: chr7-92244589;