7-92671549-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001145306.2(CDK6):c.538-14G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0312 in 1,512,180 control chromosomes in the GnomAD database, including 2,722 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.036 (354 hom., cov: 32)
  • Exomes 𝑓: 0.031 (2368 hom.)
• Consequence: CDK6 NM_001145306.2 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.84

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 7-92671549-C-T is Benign according to our data. Variant chr7-92671549-C-T is described in ClinVar as [Benign]. Clinvar id is 1291635.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.316 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDK6	NM_001145306.2	c.538-14G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000424848.3
CDK6	NM_001259.8	c.538-14G>A		splice_polypyrimidine_tract_variant, intron_variant
CDK6	XM_047419716.1	c.538-14G>A		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDK6	ENST00000424848.3	c.538-14G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001145306.2	P1
CDK6	ENST00000265734.8	c.538-14G>A		splice_polypyrimidine_tract_variant, intron_variant		1		P1
CDK6	ENST00000473078.1	n.86-14G>A		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0357 AC: 5427 AN: 152168 Hom.: 356 Cov.: 32

Gnomad AFR AF: 0.0192

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0504

Gnomad ASJ AF: 0.0317

Gnomad EAS AF: 0.329

Gnomad SAS AF: 0.0623

Gnomad FIN AF: 0.0258

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0197

Gnomad OTH AF: 0.0483

GnomAD3 exomes AF: 0.0543 AC: 10536 AN: 193982 Hom.: 1019 AF XY: 0.0516 AC XY: 5435 AN XY: 105386

Gnomad AFR exome AF: 0.0196

Gnomad AMR exome AF: 0.0771

Gnomad ASJ exome AF: 0.0290

Gnomad EAS exome AF: 0.353

Gnomad SAS exome AF: 0.0518

Gnomad FIN exome AF: 0.0270

Gnomad NFE exome AF: 0.0202

Gnomad OTH exome AF: 0.0458

GnomAD4 exome AF: 0.0307 AC: 41733 AN: 1359894 Hom.: 2368 Cov.: 22 AF XY: 0.0310 AC XY: 20945 AN XY: 676170

Gnomad4 AFR exome AF: 0.0187

Gnomad4 AMR exome AF: 0.0716

Gnomad4 ASJ exome AF: 0.0311

Gnomad4 EAS exome AF: 0.306

Gnomad4 SAS exome AF: 0.0545

Gnomad4 FIN exome AF: 0.0267

Gnomad4 NFE exome AF: 0.0183

Gnomad4 OTH exome AF: 0.0434

GnomAD4 genome AF: 0.0356 AC: 5427 AN: 152286 Hom.: 354 Cov.: 32 AF XY: 0.0376 AC XY: 2803 AN XY: 74458

Gnomad4 AFR AF: 0.0192

Gnomad4 AMR AF: 0.0507

Gnomad4 ASJ AF: 0.0317

Gnomad4 EAS AF: 0.329

Gnomad4 SAS AF: 0.0621

Gnomad4 FIN AF: 0.0258

Gnomad4 NFE AF: 0.0197

Gnomad4 OTH AF: 0.0478

Alfa AF: 0.0217 Hom.: 30

Bravo AF: 0.0396

Asia WGS AF: 0.167 AC: 581 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	0.064
Dann	Benign	0.76

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

Publications

LitVar

Other links and lift over

dbSNP: rs2301557; hg19: chr7-92300863; COSMIC: COSV56004932;