rs42046

Variant names:

• chr7-92622889-C-G
• rs42046
• NM_001145306.2:c.698+147G>C

Your query was ambiguous. Multiple possible variants found:

• chr7-92622889-C-G
• chr7-92622889-C-A
• chr7-92622889-C-T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001145306.2(CDK6):​c.698+147G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 593,384 control chromosomes in the GnomAD database, including 17,529 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3930 hom., cov: 31)
  • Exomes 𝑓: 0.23 (13599 hom.)
• Consequence: CDK6 NM_001145306.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.68
• Publications: 16 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25).
• BP6: Variant 7-92622889-C-G is Benign according to our data. Variant chr7-92622889-C-G is described in ClinVar as Benign. ClinVar VariationId is 1250250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.279 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.698+147G>C		intron	N/A	NP_001138778.1	Q00534
	CDK6	NM_001259.8		c.698+147G>C		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.698+147G>C		intron	N/A	ENSP00000397087.3	Q00534
	CDK6	ENST00000265734.8	TSL:1	c.698+147G>C		intron	N/A	ENSP00000265734.4	Q00534
	CDK6	ENST00000906280.1		c.698+147G>C		intron	N/A	ENSP00000576339.1

Frequencies

GnomAD3 genomes AF: 0.206 AC: 31304 AN: 151726 Hom.: 3938 Cov.: 31

Gnomad AFR AF: 0.0822

Gnomad AMI AF: 0.326

Gnomad AMR AF: 0.209

Gnomad ASJ AF: 0.345

Gnomad EAS AF: 0.0227

Gnomad SAS AF: 0.137

Gnomad FIN AF: 0.247

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.283

Gnomad OTH AF: 0.254

GnomAD4 exome AF: 0.233 AC: 103030 AN: 441540 Hom.: 13599 AF XY: 0.230 AC XY: 53396 AN XY: 232374

African (AFR) AF: 0.0823 AC: 1001 AN: 12160

American (AMR) AF: 0.182 AC: 3391 AN: 18630

Ashkenazi Jewish (ASJ) AF: 0.348 AC: 4507 AN: 12946

East Asian (EAS) AF: 0.0236 AC: 714 AN: 30274

South Asian (SAS) AF: 0.135 AC: 5431 AN: 40270

European-Finnish (FIN) AF: 0.254 AC: 10667 AN: 42008

Middle Eastern (MID) AF: 0.282 AC: 893 AN: 3168

European-Non Finnish (NFE) AF: 0.273 AC: 70309 AN: 257424

Other (OTH) AF: 0.248 AC: 6117 AN: 24660

GnomAD4 genome AF: 0.206 AC: 31292 AN: 151844 Hom.: 3930 Cov.: 31 AF XY: 0.204 AC XY: 15135 AN XY: 74162

African (AFR) AF: 0.0821 AC: 3405 AN: 41474

American (AMR) AF: 0.209 AC: 3171 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.345 AC: 1196 AN: 3464

East Asian (EAS) AF: 0.0228 AC: 117 AN: 5140

South Asian (SAS) AF: 0.137 AC: 662 AN: 4816

European-Finnish (FIN) AF: 0.247 AC: 2601 AN: 10510

Middle Eastern (MID) AF: 0.367 AC: 108 AN: 294

European-Non Finnish (NFE) AF: 0.283 AC: 19206 AN: 67920

Other (OTH) AF: 0.251 AC: 529 AN: 2108

Alfa AF: 0.147 Hom.: 306

Bravo AF: 0.201

Asia WGS AF: 0.0930 AC: 324 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	-0.25
CADD	Benign	20
DANN	Benign	0.81
PhyloP100		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs42046; hg19: chr7-92252203; COSMIC: COSV56014940; COSMIC: COSV56014940;