6-36684247-G-C

Variant names:

• chr6-36684247-G-C
• rs1260849045
• NM_000389.5:c.146G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000389.5(CDKN1A):​c.146G>C​(p.Trp49Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDKN1A NM_000389.5 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 7.36
• Publications: 1 publications found

Genes affected

CDKN1A (HGNC:1784): (cyclin dependent kinase inhibitor 1A) This gene encodes a potent cyclin-dependent kinase inhibitor. The encoded protein binds to and inhibits the activity of cyclin-cyclin-dependent kinase2 or -cyclin-dependent kinase4 complexes, and thus functions as a regulator of cell cycle progression at G1. The expression of this gene is tightly controlled by the tumor suppressor protein p53, through which this protein mediates the p53-dependent cell cycle G1 phase arrest in response to a variety of stress stimuli. This protein can interact with proliferating cell nuclear antigen, a DNA polymerase accessory factor, and plays a regulatory role in S phase DNA replication and DNA damage repair. This protein was reported to be specifically cleaved by CASP3-like caspases, which thus leads to a dramatic activation of cyclin-dependent kinase2, and may be instrumental in the execution of apoptosis following caspase activation. Mice that lack this gene have the ability to regenerate damaged or missing tissue. Multiple alternatively spliced variants have been found for this gene. [provided by RefSeq, Sep 2015]

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.95

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000389.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1A	NM_000389.5	MANE Select	c.146G>C	p.Trp49Ser	missense	Exon 2 of 3	NP_000380.1	P38936
	CDKN1A	NM_001291549.3		c.248G>C	p.Trp83Ser	missense	Exon 3 of 4	NP_001278478.1
	CDKN1A	NM_001374509.1		c.248G>C	p.Trp83Ser	missense	Exon 3 of 4	NP_001361438.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1A	ENST00000244741.10	TSL:1 MANE Select	c.146G>C	p.Trp49Ser	missense	Exon 2 of 3	ENSP00000244741.6	P38936
	CDKN1A	ENST00000405375.5	TSL:1	c.146G>C	p.Trp49Ser	missense	Exon 2 of 3	ENSP00000384849.1	P38936
	CDKN1A	ENST00000373711.4	TSL:5	c.146G>C	p.Trp49Ser	missense	Exon 3 of 4	ENSP00000362815.1	P38936

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		7.4
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-13	D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.75		Gain of disorder (P = 0.0062)
MVP		0.99
MPC		0.89
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.89
Mutation Taster		=7/93	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1260849045; hg19: chr6-36652024;