12-57749476-C-T

Position:

• chr12-57749476-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_000075.4(CDK4):​c.661G>A​(p.Asp221Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000768 in 1,614,042 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000083 (0 hom.)
• Consequence: CDK4 NM_000075.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:3 O:1
• Conservation: PhyloP100: 5.23

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]

TSPAN31 (HGNC:10539): (tetraspanin 31) The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. This encoded protein is thought to be involved in growth-related cellular processes. This gene is associated with tumorigenesis and osteosarcoma. [provided by RefSeq, Jul 2008]

CDK4 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 12-57749476-C-T is Benign according to our data. Variant chr12-57749476-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 133876.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=6, not_provided=1}.
• BS2: High AC in GnomAdExome4 at 122 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDK4	NM_000075.4	c.661G>A	p.Asp221Asn	missense_variant	6/8	ENST00000257904.11	NP_000066.1
TSPAN31	NM_005981.5	c.*2186C>T		3_prime_UTR_variant	6/6	ENST00000257910.8	NP_005972.1
TSPAN31	NM_001330169.2	c.*2186C>T		3_prime_UTR_variant	6/6		NP_001317098.1
TSPAN31	NM_001330168.2	c.*2186C>T		3_prime_UTR_variant	4/4		NP_001317097.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDK4	ENST00000257904.11	c.661G>A	p.Asp221Asn	missense_variant	6/8	1	NM_000075.4	ENSP00000257904.5
TSPAN31	ENST00000257910.8	c.*2186C>T		3_prime_UTR_variant	6/6	1	NM_005981.5	ENSP00000257910.3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000477 AC: 12 AN: 251442 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135898

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000835 AC: 122 AN: 1461856 Hom.: 0 Cov.: 31 AF XY: 0.0000839 AC XY: 61 AN XY: 727226

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000106

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74348

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Melanoma, cutaneous malignant, susceptibility to, 3 Uncertain:3

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	Mendelics	Jul 02, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jun 27, 2017	- -

not specified Benign:2 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 13, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 23, 2022	Variant summary: CDK4 c.661G>A (p.Asp221Asn) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251442 control chromosomes, predominantly at a frequency of 0.00011 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 6-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 a benign polymorphism found primarily in populations of Non-Finnish European origin. c.661G>A has been reported in the literature in individuals with breast cancer and brain metastasis without evidence of causality (Guindalini_2022, Diossy_2018). These reports do not provide unequivocal conclusions about association of the variant with Cutaneous Malignant Melanoma. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=5) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 16, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 24728327, 20668451) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	- -

Familial melanoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 16, 2024

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 221 of the CDK4 protein (p.Asp221Asn). This variant is present in population databases (rs587778187, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with CDK4-related conditions. ClinVar contains an entry for this variant (Variation ID: 133876). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 29, 2024

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.39
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T;.;T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Benign	0.039	D
MetaRNN	Uncertain	0.53	D;D;D
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	0.91	L;.;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.5	N;N;N
REVEL	Uncertain	0.33
Sift	Benign	0.11	T;T;T
Sift4G	Benign	0.12	T;T;.
Polyphen		0.97	D;.;.
Vest4		0.55
MutPred		0.70		Gain of ubiquitination at K225 (P = 0.1446);.;.;
MVP		0.52
MPC		0.83
ClinPred		0.29	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.52
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs587778187; hg19: chr12-58143259; COSMIC: COSV57276294; COSMIC: COSV57276294;