7-92618225-A-G

Variant names:

• chr7-92618225-A-G
• rs3731373
• NM_001145306.2:c.699-18T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001145306.2(CDK6):​c.699-18T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0514 in 1,613,104 control chromosomes in the GnomAD database, including 2,337 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (181 hom., cov: 32)
  • Exomes 𝑓: 0.052 (2156 hom.)
• Consequence: CDK6 NM_001145306.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0160
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 7-92618225-A-G is Benign according to our data. Variant chr7-92618225-A-G is described in ClinVar as [Benign]. Clinvar id is 1226582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0568 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK6	NM_001145306.2	c.699-18T>C		intron_variant	Intron 6 of 7	ENST00000424848.3	NP_001138778.1
CDK6	NM_001259.8	c.699-18T>C		intron_variant	Intron 6 of 7		NP_001250.1
CDK6	XM_047419716.1	c.699-18T>C		intron_variant	Intron 6 of 7		XP_047275672.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK6	ENST00000424848.3	c.699-18T>C		intron_variant	Intron 6 of 7	1	NM_001145306.2	ENSP00000397087.3
CDK6	ENST00000265734.8	c.699-18T>C		intron_variant	Intron 6 of 7	1		ENSP00000265734.4
CDK6	ENST00000467166.1	n.53T>C		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes AF: 0.0425 AC: 6471 AN: 152192 Hom.: 182 Cov.: 32

Gnomad AFR AF: 0.0201

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.0375

Gnomad ASJ AF: 0.0848

Gnomad EAS AF: 0.00655

Gnomad SAS AF: 0.0325

Gnomad FIN AF: 0.0446

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0583

Gnomad OTH AF: 0.0483

GnomAD2 exomes AF: 0.0458 AC: 11479 AN: 250714 AF XY: 0.0470

Gnomad AFR exome AF: 0.0197

Gnomad AMR exome AF: 0.0266

Gnomad ASJ exome AF: 0.0834

Gnomad EAS exome AF: 0.00397

Gnomad FIN exome AF: 0.0437

Gnomad NFE exome AF: 0.0616

Gnomad OTH exome AF: 0.0510

GnomAD4 exome AF: 0.0523 AC: 76397 AN: 1460794 Hom.: 2156 Cov.: 31 AF XY: 0.0525 AC XY: 38128 AN XY: 726730

African (AFR) AF: 0.0180 AC: 602 AN: 33408

American (AMR) AF: 0.0283 AC: 1262 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.0824 AC: 2152 AN: 26116

East Asian (EAS) AF: 0.00189 AC: 75 AN: 39684

South Asian (SAS) AF: 0.0353 AC: 3040 AN: 86198

European-Finnish (FIN) AF: 0.0462 AC: 2467 AN: 53390

Middle Eastern (MID) AF: 0.0593 AC: 333 AN: 5620

European-Non Finnish (NFE) AF: 0.0571 AC: 63443 AN: 1111372

Other (OTH) AF: 0.0501 AC: 3023 AN: 60348

GnomAD4 genome AF: 0.0425 AC: 6477 AN: 152310 Hom.: 181 Cov.: 32 AF XY: 0.0413 AC XY: 3076 AN XY: 74464

African (AFR) AF: 0.0201 AC: 835 AN: 41566

American (AMR) AF: 0.0374 AC: 573 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0848 AC: 294 AN: 3468

East Asian (EAS) AF: 0.00656 AC: 34 AN: 5182

South Asian (SAS) AF: 0.0333 AC: 161 AN: 4828

European-Finnish (FIN) AF: 0.0446 AC: 474 AN: 10618

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0583 AC: 3968 AN: 68028

Other (OTH) AF: 0.0483 AC: 102 AN: 2112

Alfa AF: 0.0563 Hom.: 431

Bravo AF: 0.0413

Asia WGS AF: 0.0300 AC: 105 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 18, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.9
DANN	Benign	0.33
PhyloP100		-0.016
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: rs3731373; hg19: chr7-92247539;