rs2237570

Variant names:

• chr7-92628940-A-T
• rs2237570
• NM_001145306.2:c.648-5854T>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_001145306.2(CDK6):​c.648-5854T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0868 in 152,150 control chromosomes in the GnomAD database, including 755 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 0.087 (755 hom., cov: 32)
• Consequence: CDK6 NM_001145306.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.05
• Publications: 9 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.172 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK6	NM_001145306.2	c.648-5854T>A		intron_variant	Intron 5 of 7	ENST00000424848.3	NP_001138778.1
CDK6	NM_001259.8	c.648-5854T>A		intron_variant	Intron 5 of 7		NP_001250.1
CDK6	XM_047419716.1	c.648-5854T>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.648-5854T>A		intron_variant	Intron 5 of 7	1	NM_001145306.2	ENSP00000397087.3
CDK6	ENST00000265734.8	c.648-5854T>A		intron_variant	Intron 5 of 7	1		ENSP00000265734.4

Frequencies

GnomAD3 genomes AF: 0.0868 AC: 13201 AN: 152032 Hom.: 754 Cov.: 32

Gnomad AFR AF: 0.0203

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.0259

Gnomad EAS AF: 0.0747

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.128

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.0776

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

GnomAD4 genome AF: 0.0868 AC: 13211 AN: 152150 Hom.: 755 Cov.: 32 AF XY: 0.0898 AC XY: 6684 AN XY: 74392

African (AFR) AF: 0.0203 AC: 842 AN: 41556

American (AMR) AF: 0.177 AC: 2706 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.0259 AC: 90 AN: 3472

East Asian (EAS) AF: 0.0749 AC: 387 AN: 5166

South Asian (SAS) AF: 0.117 AC: 566 AN: 4822

European-Finnish (FIN) AF: 0.128 AC: 1358 AN: 10592

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.104 AC: 7053 AN: 67966

Other (OTH) AF: 0.0773 AC: 163 AN: 2110

Alfa AF: 0.0959 Hom.: 106

Bravo AF: 0.0864

Asia WGS AF: 0.102 AC: 355 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	15
DANN	Benign	0.92
PhyloP100		1.1
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: rs2237570; hg19: chr7-92258254;