rs4729049

Variant names:

• chr7-92747869-T-C
• rs4729049
• NM_001145306.2:c.370-22076A>G

Variant summary

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

The NM_001145306.2(CDK6):​c.370-22076A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 152,204 control chromosomes in the GnomAD database, including 1,364 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 0.12 (1364 hom., cov: 32)
• Consequence: CDK6 NM_001145306.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.269
• Publications: 15 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=-0.87).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.282 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK6	NM_001145306.2	c.370-22076A>G		intron_variant	Intron 3 of 7	ENST00000424848.3	NP_001138778.1
CDK6	NM_001259.8	c.370-22076A>G		intron_variant	Intron 3 of 7		NP_001250.1
CDK6	XM_047419716.1	c.370-22076A>G		intron_variant	Intron 3 of 7		XP_047275672.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK6	ENST00000424848.3	c.370-22076A>G		intron_variant	Intron 3 of 7	1	NM_001145306.2	ENSP00000397087.3
CDK6	ENST00000265734.8	c.370-22076A>G		intron_variant	Intron 3 of 7	1		ENSP00000265734.4

Frequencies

GnomAD3 genomes AF: 0.124 AC: 18921 AN: 152086 Hom.: 1363 Cov.: 32

Gnomad AFR AF: 0.153

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.0861

Gnomad ASJ AF: 0.0710

Gnomad EAS AF: 0.162

Gnomad SAS AF: 0.296

Gnomad FIN AF: 0.162

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.0986

Gnomad OTH AF: 0.123

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.124 AC: 18942 AN: 152204 Hom.: 1364 Cov.: 32 AF XY: 0.130 AC XY: 9675 AN XY: 74412

African (AFR) AF: 0.153 AC: 6368 AN: 41520

American (AMR) AF: 0.0858 AC: 1313 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0710 AC: 246 AN: 3466

East Asian (EAS) AF: 0.163 AC: 843 AN: 5168

South Asian (SAS) AF: 0.294 AC: 1422 AN: 4830

European-Finnish (FIN) AF: 0.162 AC: 1711 AN: 10594

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.0986 AC: 6706 AN: 68008

Other (OTH) AF: 0.127 AC: 268 AN: 2114

Alfa AF: 0.106 Hom.: 1354

Bravo AF: 0.115

Asia WGS AF: 0.271 AC: 940 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	10
DANN	Benign	0.86
PhyloP100		-0.27
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: rs4729049; hg19: chr7-92377183;