rs42041

Variant names:

• chr7-92617430-C-G
• rs42041
• NM_001145306.2:c.834+642G>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.834+642G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.205 in 152,142 control chromosomes in the GnomAD database, including 3,556 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 (3556 hom., cov: 32)
• Consequence: CDK6 NM_001145306.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.48
• Publications: 50 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=-0.97).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.252 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK6	NM_001145306.2	c.834+642G>C		intron_variant	Intron 7 of 7	ENST00000424848.3	NP_001138778.1
CDK6	NM_001259.8	c.834+642G>C		intron_variant	Intron 7 of 7		NP_001250.1
CDK6	XM_047419716.1	c.834+642G>C		intron_variant	Intron 7 of 7		XP_047275672.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK6	ENST00000424848.3	c.834+642G>C		intron_variant	Intron 7 of 7	1	NM_001145306.2	ENSP00000397087.3
CDK6	ENST00000265734.8	c.834+642G>C		intron_variant	Intron 7 of 7	1		ENSP00000265734.4
CDK6	ENST00000467166.1	n.206+642G>C		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes AF: 0.205 AC: 31232 AN: 152024 Hom.: 3559 Cov.: 32

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.323

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.296

Gnomad EAS AF: 0.0262

Gnomad SAS AF: 0.108

Gnomad FIN AF: 0.226

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.255

Gnomad OTH AF: 0.226

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

GnomAD4 genome AF: 0.205 AC: 31238 AN: 152142 Hom.: 3556 Cov.: 32 AF XY: 0.203 AC XY: 15077 AN XY: 74376

African (AFR) AF: 0.152 AC: 6321 AN: 41514

American (AMR) AF: 0.175 AC: 2681 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.296 AC: 1026 AN: 3468

East Asian (EAS) AF: 0.0262 AC: 136 AN: 5186

South Asian (SAS) AF: 0.108 AC: 518 AN: 4818

European-Finnish (FIN) AF: 0.226 AC: 2391 AN: 10586

Middle Eastern (MID) AF: 0.282 AC: 83 AN: 294

European-Non Finnish (NFE) AF: 0.255 AC: 17315 AN: 67966

Other (OTH) AF: 0.224 AC: 472 AN: 2106

Alfa AF: 0.237 Hom.: 586

Bravo AF: 0.201

Asia WGS AF: 0.0910 AC: 317 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.83
DANN	Benign	0.65
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs42041; hg19: chr7-92246744;