NM_001145306.2:c.*32G>A

Variant names:

• chr7-92615108-C-T
• rs42039
• NM_001145306.2:c.*32G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001145306.2(CDK6):​c.*32G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.219 in 1,610,222 control chromosomes in the GnomAD database, including 41,796 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 0.19 (3194 hom., cov: 32)
  • Exomes 𝑓: 0.22 (38602 hom.)
• Consequence: CDK6 NM_001145306.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.25
• Publications: 51 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.249 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK6	NM_001145306.2	c.*32G>A		3_prime_UTR_variant	Exon 8 of 8	ENST00000424848.3	NP_001138778.1
CDK6	NM_001259.8	c.*32G>A		3_prime_UTR_variant	Exon 8 of 8		NP_001250.1
CDK6	XM_047419716.1	c.*32G>A		3_prime_UTR_variant	Exon 8 of 8		XP_047275672.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK6	ENST00000424848.3	c.*32G>A		3_prime_UTR_variant	Exon 8 of 8	1	NM_001145306.2	ENSP00000397087.3
CDK6	ENST00000265734.8	c.*32G>A		3_prime_UTR_variant	Exon 8 of 8	1		ENSP00000265734.4
CDK6	ENST00000467166.1	n.385G>A		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes AF: 0.189 AC: 28707 AN: 151982 Hom.: 3198 Cov.: 32

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.323

Gnomad AMR AF: 0.168

Gnomad ASJ AF: 0.285

Gnomad EAS AF: 0.0162

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.223

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.252

Gnomad OTH AF: 0.218

GnomAD2 exomes AF: 0.188 AC: 46719 AN: 248740 AF XY: 0.190

Gnomad AFR exome AF: 0.0995

Gnomad AMR exome AF: 0.126

Gnomad ASJ exome AF: 0.284

Gnomad EAS exome AF: 0.0137

Gnomad FIN exome AF: 0.231

Gnomad NFE exome AF: 0.249

Gnomad OTH exome AF: 0.218

GnomAD4 exome AF: 0.223 AC: 324622 AN: 1458122 Hom.: 38602 Cov.: 31 AF XY: 0.220 AC XY: 159420 AN XY: 725366

African (AFR) AF: 0.0940 AC: 3138 AN: 33396

American (AMR) AF: 0.132 AC: 5899 AN: 44584

Ashkenazi Jewish (ASJ) AF: 0.282 AC: 7356 AN: 26090

East Asian (EAS) AF: 0.0158 AC: 628 AN: 39670

South Asian (SAS) AF: 0.115 AC: 9938 AN: 86046

European-Finnish (FIN) AF: 0.232 AC: 12351 AN: 53322

Middle Eastern (MID) AF: 0.204 AC: 944 AN: 4632

European-Non Finnish (NFE) AF: 0.244 AC: 271337 AN: 1110202

Other (OTH) AF: 0.217 AC: 13031 AN: 60180

GnomAD4 genome AF: 0.189 AC: 28710 AN: 152100 Hom.: 3194 Cov.: 32 AF XY: 0.186 AC XY: 13858 AN XY: 74362

African (AFR) AF: 0.103 AC: 4261 AN: 41518

American (AMR) AF: 0.168 AC: 2567 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.285 AC: 990 AN: 3468

East Asian (EAS) AF: 0.0163 AC: 84 AN: 5160

South Asian (SAS) AF: 0.104 AC: 502 AN: 4822

European-Finnish (FIN) AF: 0.223 AC: 2362 AN: 10576

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.252 AC: 17111 AN: 67956

Other (OTH) AF: 0.216 AC: 456 AN: 2112

Alfa AF: 0.229 Hom.: 14708

Bravo AF: 0.183

Asia WGS AF: 0.0850 AC: 298 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 18, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.7
DANN	Benign	0.51
PhyloP100		-1.3
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: rs42039; hg19: chr7-92244422; COSMIC: COSV56004410;