chr6-36686574-T-A

Variant names:

• chr6-36686574-T-A
• rs6457937
• NM_000389.5:c.*774T>A

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_Moderate

The NM_000389.5(CDKN1A):c.*774T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The gene CDKN1A is a tumor suppressor gene (CancerMine: 79 TSG, 80 oncogene, 4 driver citations). The gene CDKN1A is a known oncogene (CancerMine: 79 TSG, 80 oncogene, 4 driver citations). The variant allele was found at a cumulative frequency of 0.00000657 (AC=1) in the gnomAD database across 152,126 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000147. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CDKN1A NM_000389.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.622
• Publications: 10 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]

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = 0.000015, AC = 1 — absent/extremely rare (O3 moderate [+2])

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CDKN1A NM_000389.5	MANE Select	c.*774T>A	3_prime_UTR	Exon 3 of 3	Prot: NP_000380.1 UniProt:
	CDKN1A NM_001291549.3		c.*774T>A	3_prime_UTR	Exon 4 of 4	Prot: NP_001278478.1
	CDKN1A NM_001374509.1		c.*774T>A	3_prime_UTR	Exon 4 of 4	Prot: NP_001361438.1

CDKN1A NM_000389.5

MANE Select

HGVSc / HGVSpc.*774T>A

Exon rankExon 3 of 3

3_prime_UTR

Prot: NP_000380.1UniProt: P38936

CDKN1A NM_001291549.3

HGVSc / HGVSpc.*774T>A

Exon rankExon 4 of 4

3_prime_UTR

Prot: NP_001278478.1

CDKN1A NM_001374509.1

HGVSc / HGVSpc.*774T>A

Exon rankExon 4 of 4

3_prime_UTR

Prot: NP_001361438.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CDKN1A ENST00000244741.10	TSL:1MANE Select	c.*774T>A	3_prime_UTR	Exon 3 of 3	Prot: ENSP00000244741.6 UniProt:
	CDKN1A ENST00000405375.5	TSL:1	c.*774T>A	3_prime_UTR	Exon 3 of 3	Prot: ENSP00000384849.1 UniProt:
	CDKN1A ENST00000373711.4	TSL:5	c.*774T>A	3_prime_UTR	Exon 4 of 4	Prot: ENSP00000362815.1 UniProt:

CDKN1A ENST00000244741.10

TSL:1MANE Select

HGVSc / HGVSpc.*774T>A

Exon rankExon 3 of 3

3_prime_UTR

Prot: ENSP00000244741.6UniProt: P38936

CDKN1A ENST00000405375.5

TSL:1

HGVSc / HGVSpc.*774T>A

Exon rankExon 3 of 3

3_prime_UTR

Prot: ENSP00000384849.1UniProt: P38936

CDKN1A ENST00000373711.4

TSL:5

HGVSc / HGVSpc.*774T>A

Exon rankExon 4 of 4

3_prime_UTR

Prot: ENSP00000362815.1UniProt: P38936

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00000657	AC:1	Hom:0	AN:152126	Cov:30
GnomAD4 exome Warning	AF: 0.00	AC:0	Hom:0	AN:81712	Cov:0
GnomAD4 genome	AF: 0.00000657	AC:1	Hom:0	AN:152126	Cov:30
TOPMed (Bravo)	AF: 0.160	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:6925	AN:14476	Cov:

Showing 5 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	1.6
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.5
DANN	Benign	0.55
GPN-Star LLR	N/A	2.3
GPN-Star score	N/A	-2.3
PhyloP100	Benign	-0.62
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.1

Showing 9 of 9 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs6457937;

hg19: chr6-36654351;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar