NM_001145306.2:c.588C>T

Variant names:

• chr7-92671485-G-A
• rs140690409
• NM_001145306.2:c.588C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_001145306.2(CDK6):​c.588C>T​(p.Tyr196Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000139 in 1,582,208 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00066 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000084 (0 hom.)
• Consequence: CDK6 NM_001145306.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.106
• Publications: 2 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 7-92671485-G-A is Benign according to our data. Variant chr7-92671485-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 717291.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.106 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK6	NM_001145306.2	c.588C>T	p.Tyr196Tyr	synonymous_variant	Exon 5 of 8	ENST00000424848.3	NP_001138778.1
CDK6	NM_001259.8	c.588C>T	p.Tyr196Tyr	synonymous_variant	Exon 5 of 8		NP_001250.1
CDK6	XM_047419716.1	c.588C>T	p.Tyr196Tyr	synonymous_variant	Exon 5 of 8		XP_047275672.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK6	ENST00000424848.3	c.588C>T	p.Tyr196Tyr	synonymous_variant	Exon 5 of 8	1	NM_001145306.2	ENSP00000397087.3
CDK6	ENST00000265734.8	c.588C>T	p.Tyr196Tyr	synonymous_variant	Exon 5 of 8	1		ENSP00000265734.4
CDK6	ENST00000473078.1	n.136C>T		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes AF: 0.000631 AC: 96 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00210

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000272 AC: 62 AN: 227764 AF XY: 0.000178

Gnomad AFR exome AF: 0.00204

Gnomad AMR exome AF: 0.000970

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000667

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000191

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000839 AC: 120 AN: 1429874 Hom.: 0 Cov.: 29 AF XY: 0.0000675 AC XY: 48 AN XY: 711308

African (AFR) AF: 0.00203 AC: 64 AN: 31578

American (AMR) AF: 0.000856 AC: 35 AN: 40880

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25346

East Asian (EAS) AF: 0.0000273 AC: 1 AN: 36568

South Asian (SAS) AF: 0.0000365 AC: 3 AN: 82148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52758

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5620

European-Non Finnish (NFE) AF: 0.00000456 AC: 5 AN: 1095992

Other (OTH) AF: 0.000203 AC: 12 AN: 58984

GnomAD4 genome AF: 0.000656 AC: 100 AN: 152334 Hom.: 1 Cov.: 32 AF XY: 0.000631 AC XY: 47 AN XY: 74490

African (AFR) AF: 0.00219 AC: 91 AN: 41574

American (AMR) AF: 0.000327 AC: 5 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68032

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000585 Hom.: 0

Bravo AF: 0.000831

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	9.5
DANN	Benign	0.69
PhyloP100		0.11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs140690409; hg19: chr7-92300799; COSMIC: COSV56008010;