12-57749249-G-C

Variant names:

• chr12-57749249-G-C
• rs143670820
• NM_000075.4:c.752C>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_000075.4(CDK4):​c.752C>G​(p.Pro251Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000123 in 1,461,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P251H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: CDK4 NM_000075.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 5.36
• Publications: 8 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1397497).
• BP6: Variant 12-57749249-G-C is Benign according to our data. Variant chr12-57749249-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 220063.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• BS2: High AC in GnomAdExome4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK4	NM_000075.4	c.752C>G	p.Pro251Arg	missense_variant	Exon 7 of 8	ENST00000257904.11	NP_000066.1
TSPAN31	NM_005981.5	c.*1959G>C		3_prime_UTR_variant	Exon 6 of 6	ENST00000257910.8	NP_005972.1
TSPAN31	NM_001330169.2	c.*1959G>C		3_prime_UTR_variant	Exon 6 of 6		NP_001317098.1
TSPAN31	NM_001330168.2	c.*1959G>C		3_prime_UTR_variant	Exon 4 of 4		NP_001317097.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK4	ENST00000257904.11	c.752C>G	p.Pro251Arg	missense_variant	Exon 7 of 8	1	NM_000075.4	ENSP00000257904.5
TSPAN31	ENST00000257910.8	c.*1959G>C		3_prime_UTR_variant	Exon 6 of 6	1	NM_005981.5	ENSP00000257910.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000518 AC: 13 AN: 250930 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461774 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727192

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.000291 AC: 13 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111932

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Jul 18, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Observed in patients with a personal and family history of pancreatic or breast cancer (PMID: 28726808, 35534704); This variant is associated with the following publications: (PMID: 26252490, 36243179, 28726808, 35534704) -

not specified Uncertain:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Melanoma, cutaneous malignant, susceptibility to, 3 Uncertain:1

Apr 12, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Sep 16, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.32	T;.;T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.0056
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.82	T;T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.77	N;.;.
PhyloP100		5.4
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.94	N;N;N
REVEL	Benign	0.031
Sift	Benign	0.24	T;T;T
Sift4G	Benign	0.46	T;T;.
Polyphen		0.0040	B;.;.
Vest4		0.33
MutPred		0.37		Loss of catalytic residue at P250 (P = 0.0185);.;.;
MVP		0.71
MPC		0.66
ClinPred		0.061	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.44
gMVP		0.37
Mutation Taster		=56/44	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs143670820; hg19: chr12-58143032;