rs3757823

Variant names:

• chr7-92674240-A-G
• rs3757823
• NM_001145306.2:c.538-2705T>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.538-2705T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.239 in 151,822 control chromosomes in the GnomAD database, including 6,497 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 0.24 (6497 hom., cov: 31)
• Consequence: CDK6 NM_001145306.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.241
• Publications: 10 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=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.477 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK6	NM_001145306.2	c.538-2705T>C		intron_variant	Intron 4 of 7	ENST00000424848.3	NP_001138778.1
CDK6	NM_001259.8	c.538-2705T>C		intron_variant	Intron 4 of 7		NP_001250.1
CDK6	XM_047419716.1	c.538-2705T>C		intron_variant	Intron 4 of 7		XP_047275672.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK6	ENST00000424848.3	c.538-2705T>C		intron_variant	Intron 4 of 7	1	NM_001145306.2	ENSP00000397087.3
CDK6	ENST00000265734.8	c.538-2705T>C		intron_variant	Intron 4 of 7	1		ENSP00000265734.4
CDK6	ENST00000473078.1	n.86-2705T>C		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes AF: 0.238 AC: 36171 AN: 151704 Hom.: 6470 Cov.: 31

Gnomad AFR AF: 0.482

Gnomad AMI AF: 0.0604

Gnomad AMR AF: 0.159

Gnomad ASJ AF: 0.159

Gnomad EAS AF: 0.492

Gnomad SAS AF: 0.298

Gnomad FIN AF: 0.153

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.223

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

GnomAD4 genome AF: 0.239 AC: 36258 AN: 151822 Hom.: 6497 Cov.: 31 AF XY: 0.242 AC XY: 17967 AN XY: 74212

African (AFR) AF: 0.483 AC: 19949 AN: 41332

American (AMR) AF: 0.159 AC: 2432 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.159 AC: 551 AN: 3464

East Asian (EAS) AF: 0.493 AC: 2545 AN: 5166

South Asian (SAS) AF: 0.298 AC: 1433 AN: 4804

European-Finnish (FIN) AF: 0.153 AC: 1618 AN: 10554

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.105 AC: 7142 AN: 67938

Other (OTH) AF: 0.228 AC: 481 AN: 2106

Alfa AF: 0.153 Hom.: 3540

Bravo AF: 0.249

Asia WGS AF: 0.419 AC: 1456 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.97
DANN	Benign	0.69
PhyloP100		-0.24
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: rs3757823; hg19: chr7-92303554;