chr7-92627591-C-T

Variant names:

• chr7-92627591-C-T
• rs2040494
• NM_001145306.2:c.648-4505G>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.648-4505G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.637 in 151,846 control chromosomes in the GnomAD database, including 32,136 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 0.64 (32136 hom., cov: 31)
• Consequence: CDK6 NM_001145306.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.353
• Publications: 18 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=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.806 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK6	NM_001145306.2	c.648-4505G>A		intron_variant	Intron 5 of 7	ENST00000424848.3	NP_001138778.1
CDK6	NM_001259.8	c.648-4505G>A		intron_variant	Intron 5 of 7		NP_001250.1
CDK6	XM_047419716.1	c.648-4505G>A		intron_variant	Intron 5 of 7		XP_047275672.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK6	ENST00000424848.3	c.648-4505G>A		intron_variant	Intron 5 of 7	1	NM_001145306.2	ENSP00000397087.3
CDK6	ENST00000265734.8	c.648-4505G>A		intron_variant	Intron 5 of 7	1		ENSP00000265734.4

Frequencies

GnomAD3 genomes AF: 0.637 AC: 96588 AN: 151728 Hom.: 32098 Cov.: 31

Gnomad AFR AF: 0.813

Gnomad AMI AF: 0.459

Gnomad AMR AF: 0.735

Gnomad ASJ AF: 0.577

Gnomad EAS AF: 0.796

Gnomad SAS AF: 0.441

Gnomad FIN AF: 0.510

Gnomad MID AF: 0.589

Gnomad NFE AF: 0.534

Gnomad OTH AF: 0.634

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

GnomAD4 genome AF: 0.637 AC: 96684 AN: 151846 Hom.: 32136 Cov.: 31 AF XY: 0.637 AC XY: 47256 AN XY: 74202

African (AFR) AF: 0.813 AC: 33685 AN: 41430

American (AMR) AF: 0.736 AC: 11208 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.577 AC: 1999 AN: 3466

East Asian (EAS) AF: 0.795 AC: 4098 AN: 5156

South Asian (SAS) AF: 0.442 AC: 2128 AN: 4814

European-Finnish (FIN) AF: 0.510 AC: 5378 AN: 10548

Middle Eastern (MID) AF: 0.589 AC: 172 AN: 292

European-Non Finnish (NFE) AF: 0.534 AC: 36268 AN: 67886

Other (OTH) AF: 0.630 AC: 1329 AN: 2108

Alfa AF: 0.587 Hom.: 13676

Bravo AF: 0.666

Asia WGS AF: 0.634 AC: 2203 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	0.73
DANN	Benign	0.32
PhyloP100		-0.35
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: rs2040494; hg19: chr7-92256905;