12-57751596-T-C

Position:

chr12-57751596-T-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_000075.4(CDK4):c.122A>G(p.Asn41Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000253 in 1,614,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00026 ( 0 hom. )

Consequence

CDK4
NM_000075.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:7

Conservation

PhyloP100: 0.223

Variant links:

Genes affected

CDK4 (HGNC:1773): (cyclin dependent kinase 4) The protein encoded by this gene is a member of the Ser/Thr protein kinase family. This protein is highly similar to the gene products of S. cerevisiae cdc28 and S. pombe cdc2. It is a catalytic subunit of the protein kinase complex that is important for cell cycle G1 phase progression. The activity of this kinase is restricted to the G1-S phase, which is controlled by the regulatory subunits D-type cyclins and CDK inhibitor p16(INK4a). This kinase was shown to be responsible for the phosphorylation of retinoblastoma gene product (Rb). Mutations in this gene as well as in its related proteins including D-type cyclins, p16(INK4a) and Rb were all found to be associated with tumorigenesis of a variety of cancers. Multiple polyadenylation sites of this gene have been reported. [provided by RefSeq, Jul 2008]

CDK4 links:

CDK4 (HGNC:):

CDK4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06802559).

BP6

Variant 12-57751596-T-C is Benign according to our data. Variant chr12-57751596-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 135822.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=7, Benign=2}.

BS2

High AC in GnomAd4 at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDK4	NM_000075.4 linkuse as main transcript	c.122A>G	p.Asn41Ser	missense_variant	2/8	ENST00000257904.11	NP_000066.1	P11802-1A0A024RBB6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDK4	ENST00000257904.11 linkuse as main transcript	c.122A>G	p.Asn41Ser	missense_variant	2/8	1	NM_000075.4	ENSP00000257904.5		P11802-1

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152000

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000107

AC:

AN:

251484

Hom.:

AF XY:

0.000110

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000158

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000265

AC:

387

AN:

1461886

Hom.:

Cov.:

AF XY:

0.000246

AC XY:

179

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000309

Gnomad4 OTH exome

AF:

0.000497

GnomAD4 genome

AF:

0.000145

AC:

AN:

152118

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000218

Hom.:

Bravo

AF:

0.000196

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000165

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Melanoma, cutaneous malignant, susceptibility to, 3

Uncertain:3Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 07, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 11, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 07, 2023	The CDK4 c.122A>G; p.Asn41Ser variant (rs144890720) is reported in the literature in individuals affected with melanoma, colorectal and breast cancer but without clear disease association (Guldberg 1997, Pritchard 2018, Tung 2015, Yurgelun 2017). This variant has also been reported with a known pathogenic mutation in another gene (Beaubier 2019). This variant is also reported in ClinVar (Variation ID: 135822) and is found in the general population with an overall allele frequency of 0.01% (32/282802 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is neutral (REVEL: 0.113) and functional analyses of the variant protein show similar protein interactions compared to wild-type but suggest that the affinity between I-kappaB-alpha may be increased which negatively effects binding (Li 2003, Li 2005). While the functional analyses suggest a benign role, due to limited clinical information, the significance of this variant is uncertain at this time. References: Beaubier N et al. Integrated genomic profiling expands clinical options for patients with cancer. Nat Biotechnol. 2019 Nov;37(11):1351-1360. PMID: 31570899. Guldberg P et al. Complete scanning of the CDK4 gene by denaturing gradient gel electrophoresis: a novel missense mutation but low overall frequency of mutations in sporadic metastatic malignant melanoma. Int J Cancer. 1997 Sep 4;72(5):780-3. PMID: 9311594. Li J et al. An NF-kappaB-specific inhibitor, IkappaBalpha, binds to and inhibits cyclin-dependent kinase 4. Biochemistry. 2003 Nov 25;42(46):13476-83. PMID: 14621993. Li J et al. Dissection of CDK4-binding and transactivation activities of p34(SEI-1) and comparison between functions of p34(SEI-1) and p16(INK4A). Biochemistry. 2005 Oct 11;44(40):13246-56. PMID: 16201750. Pritchard AL et al. Germline mutations in candidate predisposition genes in individuals with cutaneous melanoma and at least two independent additional primary cancers. PLoS One. 2018 Apr 11;13(4):e0194098. PMID: 29641532. Tung N et al. Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer. 2015 Jan 1;121(1):25-33. PMID: 25186627. Yurgelun MB et al. Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. J Clin Oncol. 2017 Apr 1;35(10):1086-1095. PMID: 28135145. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

not specified

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 01, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2023	Variant summary: CDK4 c.122A>G (p.Asn41Ser) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 251484 control chromosomes (gnomAD). The observed variant frequency is approximately 5-fold of the estimated maximal expected allele frequency for a pathogenic variant in CDK4 causing Cutaneous Malignant Melanoma phenotype (2e-05), strongly suggesting that the variant is benign. c.122A>G has been reported in the literature in individuals affected with Cutaneous Malignant Melanoma, Lynch syndrome and breast cancer (e.g. Guldberg_1997, Tung_2015, Yurgelun_2015, Pritchard_2018). These reports do not provide unequivocal conclusions about association of the variant with Cutaneous Malignant Melanoma. A co-occurrence with a pathogenic variant has been reported (SDHB c.268C>T, p.R90X; Beaubier_2019). Experimental evidence evaluating an impact on protein function demonstrated the variant does not affect interaction with p16, the RM29 mutant of SEI-1, cyclin D2 and other INK4 proteins but may contribute negatively to I-kappaB-alpha binding (Li_2003, Li_2005). Nine submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=4) or benign/likely benign (n=6). Based on the evidence outlined above, the variant was classified as likely benign. -

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 03, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 22, 2024	Observed in individuals with a personal or family history of melanoma, breast, or other cancers (PMID: 9311594, 25186627, 25980754, 29641532); Published functional studies are inconclusive: does not disrupt CDK4 binding to CDKN2C or affect interaction with p16, cyclin D2, SEI-1 RM 29 or other CDK4 partner proteins; however, it may negatively impact binding with I-kappaB-alpha, an inhibitor of nuclear factor-kappaB (PMID: 14621993, 19888216, 25416956); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 12358822, 28575754, 25186627, 29641532, 29124743, 11828258, 19888216, 28135145, 9311594, 14621993, 12731669, 25980754, 16201750, 25416956, 26252490, 19139070, 24162924, 32980694, 34426522, Tabar2022[article], 35113472, 31570899, 36243179) -

CDK4-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 18, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary cancer-predisposing syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 08, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Familial melanoma

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Benign

0.78

DEOGEN2

Benign

0.19

T;T;.;T;.

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.71

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.73

T;T;T;T;T

M_CAP

Benign

0.0065

MetaRNN

Benign

0.068

T;T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.17

.;N;.;.;.

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.080

N;N;N;N;N

REVEL

Benign

0.11

Sift

Benign

0.58

T;T;T;T;T

Sift4G

Benign

0.40

T;T;T;.;.

Polyphen

0.0020

.;B;.;.;.

Vest4

0.67

MVP

0.66

MPC

0.49

ClinPred

0.024

GERP RS

-0.066

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.17

gMVP

0.19

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over