7-92819979-C-A

Variant names:

• chr7-92819979-C-A
• rs10246604
• NM_001145306.2:c.233+13112G>T

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+13112G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.139 in 151,710 control chromosomes in the GnomAD database, including 2,418 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 0.14 (2418 hom., cov: 32)
• Consequence: CDK6 NM_001145306.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.390
• Publications: 4 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=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.301 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK6	NM_001145306.2	c.233+13112G>T		intron_variant	Intron 2 of 7	ENST00000424848.3	NP_001138778.1
CDK6	NM_001259.8	c.233+13112G>T		intron_variant	Intron 2 of 7		NP_001250.1
CDK6	XM_047419716.1	c.233+13112G>T		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+13112G>T		intron_variant	Intron 2 of 7	1	NM_001145306.2	ENSP00000397087.3
CDK6	ENST00000265734.8	c.233+13112G>T		intron_variant	Intron 2 of 7	1		ENSP00000265734.4

Frequencies

GnomAD3 genomes AF: 0.139 AC: 21090 AN: 151592 Hom.: 2405 Cov.: 32

Gnomad AFR AF: 0.305

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.0891

Gnomad ASJ AF: 0.0441

Gnomad EAS AF: 0.0806

Gnomad SAS AF: 0.264

Gnomad FIN AF: 0.0442

Gnomad MID AF: 0.0801

Gnomad NFE AF: 0.0667

Gnomad OTH AF: 0.127

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

GnomAD4 genome AF: 0.139 AC: 21147 AN: 151710 Hom.: 2418 Cov.: 32 AF XY: 0.140 AC XY: 10393 AN XY: 74162

African (AFR) AF: 0.306 AC: 12644 AN: 41358

American (AMR) AF: 0.0888 AC: 1353 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.0441 AC: 153 AN: 3468

East Asian (EAS) AF: 0.0812 AC: 419 AN: 5160

South Asian (SAS) AF: 0.263 AC: 1263 AN: 4806

European-Finnish (FIN) AF: 0.0442 AC: 465 AN: 10518

Middle Eastern (MID) AF: 0.0828 AC: 24 AN: 290

European-Non Finnish (NFE) AF: 0.0667 AC: 4528 AN: 67860

Other (OTH) AF: 0.131 AC: 275 AN: 2106

Alfa AF: 0.0821 Hom.: 886

Bravo AF: 0.145

Asia WGS AF: 0.231 AC: 805 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.36
DANN	Benign	0.29
PhyloP100		-0.39
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: rs10246604; hg19: chr7-92449293;