6-36686574-T-C

Position:

• chr6-36686574-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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 frequency of 0.981 in 233,950 control chromosomes in the GnomAD database, including 112,554 homozygotes. In-silico tool predicts a benign outcome for this variant. 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

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.987 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN1A	NM_000389.5	c.*774T>C		3_prime_UTR_variant	3/3	ENST00000244741.10	NP_000380.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKN1A	ENST00000244741.10	c.*774T>C		3_prime_UTR_variant	3/3	1	NM_000389.5	ENSP00000244741.6
CDKN1A	ENST00000405375.5	c.*774T>C		3_prime_UTR_variant	3/3	1		ENSP00000384849.1
CDKN1A	ENST00000448526.6	c.*774T>C		3_prime_UTR_variant	4/4	3		ENSP00000409259.3
CDKN1A	ENST00000615513.4	c.*774T>C		3_prime_UTR_variant	3/3	2		ENSP00000482768.1

Frequencies

GnomAD3 genomes AF: 0.981 AC: 149246 AN: 152120 Hom.: 73231 Cov.: 30

Gnomad AFR AF: 0.995

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.984

Gnomad ASJ AF: 0.978

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.963

Gnomad FIN AF: 0.971

Gnomad MID AF: 0.984

Gnomad NFE AF: 0.974

Gnomad OTH AF: 0.977

GnomAD4 exome AF: 0.980 AC: 80109 AN: 81712 Hom.: 39264 Cov.: 0 AF XY: 0.980 AC XY: 36949 AN XY: 37700

Gnomad4 AFR exome AF: 0.995

Gnomad4 AMR exome AF: 0.990

Gnomad4 ASJ exome AF: 0.976

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.964

Gnomad4 FIN exome AF: 0.978

Gnomad4 NFE exome AF: 0.975

Gnomad4 OTH exome AF: 0.984

GnomAD4 genome AF: 0.981 AC: 149364 AN: 152238 Hom.: 73290 Cov.: 30 AF XY: 0.980 AC XY: 72969 AN XY: 74424

Gnomad4 AFR AF: 0.995

Gnomad4 AMR AF: 0.984

Gnomad4 ASJ AF: 0.978

Gnomad4 EAS AF: 0.998

Gnomad4 SAS AF: 0.962

Gnomad4 FIN AF: 0.971

Gnomad4 NFE AF: 0.974

Gnomad4 OTH AF: 0.977

Alfa AF: 0.974 Hom.: 5469

Bravo AF: 0.984

Asia WGS AF: 0.988 AC: 3435 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.9
DANN	Benign	0.48
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs6457937; hg19: chr6-36654351;