NM_000389.5:c.*774T>C

Variant names:

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

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -12 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_Strong

The NM_000389.5(CDKN1A):c.*774T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.981 (AC=229,473) in the gnomAD database across 233,950 control chromosomes, including 112,554 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.987. 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 0.98 (73290 hom., cov: 30)
  • Exomes 𝑓: 0.98 (39264 hom.)
• 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 ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -12 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.9870 — exceeds 5%% threshold (BA1 applied)

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>C	3_prime_UTR	Exon 3 of 3	Prot: NP_000380.1 UniProt:
	CDKN1A NM_001291549.3		c.*774T>C	3_prime_UTR	Exon 4 of 4	Prot: NP_001278478.1
	CDKN1A NM_001374509.1		c.*774T>C	3_prime_UTR	Exon 4 of 4	Prot: NP_001361438.1

CDKN1A NM_000389.5

MANE Select

HGVSc / HGVSpc.*774T>C

Exon rankExon 3 of 3

3_prime_UTR

Prot: NP_000380.1UniProt: P38936

CDKN1A NM_001291549.3

HGVSc / HGVSpc.*774T>C

Exon rankExon 4 of 4

3_prime_UTR

Prot: NP_001278478.1

CDKN1A NM_001374509.1

HGVSc / HGVSpc.*774T>C

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>C	3_prime_UTR	Exon 3 of 3	Prot: ENSP00000244741.6 UniProt:
	CDKN1A ENST00000405375.5	TSL:1	c.*774T>C	3_prime_UTR	Exon 3 of 3	Prot: ENSP00000384849.1 UniProt:
	CDKN1A ENST00000373711.4	TSL:5	c.*774T>C	3_prime_UTR	Exon 4 of 4	Prot: ENSP00000362815.1 UniProt:

CDKN1A ENST00000244741.10

TSL:1MANE Select

HGVSc / HGVSpc.*774T>C

Exon rankExon 3 of 3

3_prime_UTR

Prot: ENSP00000244741.6UniProt: P38936

CDKN1A ENST00000405375.5

TSL:1

HGVSc / HGVSpc.*774T>C

Exon rankExon 3 of 3

3_prime_UTR

Prot: ENSP00000384849.1UniProt: P38936

CDKN1A ENST00000373711.4

TSL:5

HGVSc / HGVSpc.*774T>C

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: 0.981	AC:149246	Hom:73231	AN:152120	Cov:30
GnomAD4 exome	AF: 0.980	AC:80109	Hom:39264	AN:81712	Cov:0
GnomAD4 genome	AF: 0.981	AC:149364	Hom:73290	AN:152238	Cov:30
TOPMed (Bravo)	AF: 0.984	AC:260499	Hom:128205	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.978	AC:14156	Hom:6925	AN:14476	Cov:
Local & regional cohorts 9 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.985	AC:2307	Hom:1138	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.998	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.967	AC:290	Hom:	AN:300	Cov:
GenomeAsia100K	AF: 0.988	AC:3435	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 1.00	AC:7228	Hom:	AN:7230	Cov:
Qatari Genome	AF: 0.983	AC:173	Hom:	AN:176	Cov:
Turkish Variome	AF: 0.979	AC:1513	Hom:740	AN:1546	Cov:
UK10K	AF: 0.974	AC:7368	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.998	AC:8945	Hom:4465	AN:8960	Cov:

Showing 14 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.516	13937	27004	0.342	12138	35542

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	2.3
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.9
DANN	Benign	0.48
GPN-Star LLR	N/A	5.0
GPN-Star score	N/A	0.31
Mutation Taster	N/A	100/0	polymorphism (auto)
PhyloP100	Benign	-0.62
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.1

Showing 10 of 10 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