rs992519

Variant names:

• chr7-92825883-A-G
• rs992519
• NM_001145306.2:c.233+7208T>C

Variant summary

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

The NM_001145306.2(CDK6):​c.233+7208T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.207 in 152,100 control chromosomes in the GnomAD database, including 4,125 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 0.21 (4125 hom., cov: 32)
• Consequence: CDK6 NM_001145306.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.343
• Publications: 6 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=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.36 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK6	NM_001145306.2	c.233+7208T>C		intron_variant	Intron 2 of 7	ENST00000424848.3	NP_001138778.1
CDK6	NM_001259.8	c.233+7208T>C		intron_variant	Intron 2 of 7		NP_001250.1
CDK6	XM_047419716.1	c.233+7208T>C		intron_variant	Intron 2 of 7		XP_047275672.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK6	ENST00000424848.3	c.233+7208T>C		intron_variant	Intron 2 of 7	1	NM_001145306.2	ENSP00000397087.3
CDK6	ENST00000265734.8	c.233+7208T>C		intron_variant	Intron 2 of 7	1		ENSP00000265734.4

Frequencies

GnomAD3 genomes AF: 0.206 AC: 31375 AN: 151982 Hom.: 4097 Cov.: 32

Gnomad AFR AF: 0.364

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.126

Gnomad EAS AF: 0.0856

Gnomad SAS AF: 0.361

Gnomad FIN AF: 0.171

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.137

Gnomad OTH AF: 0.189

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

GnomAD4 genome AF: 0.207 AC: 31462 AN: 152100 Hom.: 4125 Cov.: 32 AF XY: 0.210 AC XY: 15645 AN XY: 74382

African (AFR) AF: 0.365 AC: 15121 AN: 41450

American (AMR) AF: 0.139 AC: 2128 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 437 AN: 3470

East Asian (EAS) AF: 0.0864 AC: 448 AN: 5184

South Asian (SAS) AF: 0.360 AC: 1740 AN: 4828

European-Finnish (FIN) AF: 0.171 AC: 1807 AN: 10594

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.137 AC: 9281 AN: 67986

Other (OTH) AF: 0.192 AC: 405 AN: 2108

Alfa AF: 0.174 Hom.: 477

Bravo AF: 0.206

Asia WGS AF: 0.272 AC: 945 AN: 3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.91
DANN	Benign	0.40
PhyloP100		-0.34
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: rs992519; hg19: chr7-92455197;