rs104894340

Variant names:

• chr12-57751647-C-A
• rs104894340
• NM_000075.4:c.71G>T

Your query was ambiguous. Multiple possible variants found:

• chr12-57751647-C-A
• chr12-57751647-C-G
• chr12-57751647-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_000075.4(CDK4):​c.71G>T​(p.Arg24Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R24H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDK4 NM_000075.4 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:3
• Conservation: PhyloP100: 6.00
• Publications: 95 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]

CDK4 Gene-Disease associations (from GenCC):

• melanoma, cutaneous malignant, susceptibility to, 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), ClinGen
• malignant pancreatic neoplasm

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-57751647-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 16929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.865

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK4	NM_000075.4	c.71G>T	p.Arg24Leu	missense_variant	Exon 2 of 8	ENST00000257904.11	NP_000066.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK4	ENST00000257904.11	c.71G>T	p.Arg24Leu	missense_variant	Exon 2 of 8	1	NM_000075.4	ENSP00000257904.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: no assertion criteria provided

Submissions by phenotype

Multiple myeloma Pathogenic:1

May 31, 2016

Database of Curated Mutations (DoCM)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Lung adenocarcinoma Pathogenic:1

May 31, 2016

Database of Curated Mutations (DoCM)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Malignant melanoma of skin Pathogenic:1

May 31, 2016

Database of Curated Mutations (DoCM)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T;D;.;T;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Pathogenic	0.86	D;D;D;D;D
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.3	.;L;.;.;.
PhyloP100		6.0
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-5.8	D;D;D;D;D
REVEL	Benign	0.24
Sift	Uncertain	0.0010	D;T;T;D;D
Sift4G	Uncertain	0.0090	D;T;D;.;.
Polyphen		0.96	.;D;.;.;.
Vest4		0.91
MutPred		0.78		Loss of ubiquitination at K22 (P = 0.044);Loss of ubiquitination at K22 (P = 0.044);Loss of ubiquitination at K22 (P = 0.044);Loss of ubiquitination at K22 (P = 0.044);Loss of ubiquitination at K22 (P = 0.044);
MVP		0.79
MPC		0.99
ClinPred		0.99	D
GERP RS		5.2
PromoterAI		0.00040	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.88
gMVP		0.91
Mutation Taster		=9/91	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.26		Position offset: -13

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs104894340; hg19: chr12-58145430; COSMIC: COSV56983700; COSMIC: COSV56983700;