7-92618019-A-G

Variant names:

• chr7-92618019-A-G
• rs42043
• NM_001145306.2:c.834+53T>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.834+53T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.232 in 1,589,610 control chromosomes in the GnomAD database, including 44,337 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (3823 hom., cov: 32)
  • Exomes 𝑓: 0.23 (40514 hom.)
• Consequence: CDK6 NM_001145306.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.406
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 7-92618019-A-G is Benign according to our data. Variant chr7-92618019-A-G is described in ClinVar as [Benign]. Clinvar id is 1233941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.252 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK6	NM_001145306.2	c.834+53T>C		intron_variant	Intron 7 of 7	ENST00000424848.3	NP_001138778.1
CDK6	NM_001259.8	c.834+53T>C		intron_variant	Intron 7 of 7		NP_001250.1
CDK6	XM_047419716.1	c.834+53T>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+53T>C		intron_variant	Intron 7 of 7	1	NM_001145306.2	ENSP00000397087.3
CDK6	ENST00000265734.8	c.834+53T>C		intron_variant	Intron 7 of 7	1		ENSP00000265734.4
CDK6	ENST00000467166.1	n.206+53T>C		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes AF: 0.216 AC: 32890 AN: 152124 Hom.: 3825 Cov.: 32

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.324

Gnomad AMR AF: 0.225

Gnomad ASJ AF: 0.297

Gnomad EAS AF: 0.112

Gnomad SAS AF: 0.116

Gnomad FIN AF: 0.231

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.255

Gnomad OTH AF: 0.237

GnomAD4 exome AF: 0.233 AC: 335169 AN: 1437368 Hom.: 40514 AF XY: 0.230 AC XY: 163862 AN XY: 713436

African (AFR) AF: 0.153 AC: 5048 AN: 33004

American (AMR) AF: 0.223 AC: 9632 AN: 43160

Ashkenazi Jewish (ASJ) AF: 0.290 AC: 7257 AN: 25046

East Asian (EAS) AF: 0.115 AC: 4534 AN: 39494

South Asian (SAS) AF: 0.123 AC: 10188 AN: 82624

European-Finnish (FIN) AF: 0.240 AC: 12562 AN: 52406

Middle Eastern (MID) AF: 0.209 AC: 1181 AN: 5660

European-Non Finnish (NFE) AF: 0.247 AC: 271017 AN: 1096566

Other (OTH) AF: 0.231 AC: 13750 AN: 59408

GnomAD4 genome AF: 0.216 AC: 32900 AN: 152242 Hom.: 3823 Cov.: 32 AF XY: 0.215 AC XY: 15979 AN XY: 74422

African (AFR) AF: 0.159 AC: 6603 AN: 41544

American (AMR) AF: 0.224 AC: 3433 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.297 AC: 1029 AN: 3470

East Asian (EAS) AF: 0.113 AC: 585 AN: 5182

South Asian (SAS) AF: 0.115 AC: 557 AN: 4832

European-Finnish (FIN) AF: 0.231 AC: 2445 AN: 10588

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

European-Non Finnish (NFE) AF: 0.255 AC: 17373 AN: 68010

Other (OTH) AF: 0.235 AC: 497 AN: 2112

Alfa AF: 0.211 Hom.: 1177

Bravo AF: 0.216

Asia WGS AF: 0.142 AC: 496 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 18, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.7
DANN	Benign	0.74
PhyloP100		-0.41
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: rs42043; hg19: chr7-92247333;