rs2301556

Variant names:

• chr7-92671273-G-A
• rs2301556
• NM_001145306.2:c.647+153C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001145306.2(CDK6):​c.647+153C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 455,712 control chromosomes in the GnomAD database, including 6,063 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3629 hom., cov: 32)
  • Exomes 𝑓: 0.11 (2434 hom.)
• Consequence: CDK6 NM_001145306.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.42
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 7-92671273-G-A is Benign according to our data. Variant chr7-92671273-G-A is described in ClinVar as Benign. ClinVar VariationId is 1242376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.372 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDK6	NM_001145306.2	MANE Select	c.647+153C>T		intron	N/A	NP_001138778.1	Q00534
	CDK6	NM_001259.8		c.647+153C>T		intron	N/A	NP_001250.1	Q00534

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDK6	ENST00000424848.3	TSL:1 MANE Select	c.647+153C>T		intron	N/A	ENSP00000397087.3	Q00534
	CDK6	ENST00000265734.8	TSL:1	c.647+153C>T		intron	N/A	ENSP00000265734.4	Q00534
	CDK6	ENST00000906280.1		c.647+153C>T		intron	N/A	ENSP00000576339.1

Frequencies

GnomAD3 genomes AF: 0.176 AC: 26713 AN: 151972 Hom.: 3618 Cov.: 32

Gnomad AFR AF: 0.377

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.0958

Gnomad ASJ AF: 0.121

Gnomad EAS AF: 0.138

Gnomad SAS AF: 0.233

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.0833

Gnomad OTH AF: 0.149

GnomAD4 exome AF: 0.111 AC: 33720 AN: 303622 Hom.: 2434 Cov.: 4 AF XY: 0.112 AC XY: 17695 AN XY: 157710

African (AFR) AF: 0.367 AC: 2953 AN: 8036

American (AMR) AF: 0.0808 AC: 715 AN: 8854

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 1230 AN: 10200

East Asian (EAS) AF: 0.151 AC: 3545 AN: 23526

South Asian (SAS) AF: 0.211 AC: 3399 AN: 16108

European-Finnish (FIN) AF: 0.121 AC: 3021 AN: 24976

Middle Eastern (MID) AF: 0.128 AC: 216 AN: 1686

European-Non Finnish (NFE) AF: 0.0852 AC: 16280 AN: 191120

Other (OTH) AF: 0.124 AC: 2361 AN: 19116

GnomAD4 genome AF: 0.176 AC: 26755 AN: 152090 Hom.: 3629 Cov.: 32 AF XY: 0.178 AC XY: 13226 AN XY: 74366

African (AFR) AF: 0.377 AC: 15614 AN: 41448

American (AMR) AF: 0.0957 AC: 1462 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 421 AN: 3472

East Asian (EAS) AF: 0.139 AC: 719 AN: 5182

South Asian (SAS) AF: 0.233 AC: 1122 AN: 4810

European-Finnish (FIN) AF: 0.127 AC: 1346 AN: 10576

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.0833 AC: 5662 AN: 68002

Other (OTH) AF: 0.155 AC: 328 AN: 2112

Alfa AF: 0.129 Hom.: 828

Bravo AF: 0.180

Asia WGS AF: 0.228 AC: 795 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.030
DANN	Benign	0.43
PhyloP100		-1.4
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: rs2301556; hg19: chr7-92300587;