6-36686574-T-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• 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]

ACMG classification

Our verdict: Benign. The variant received -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.

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.*774T>C		3_prime_UTR	Exon 3 of 3	NP_000380.1
	CDKN1A	NM_001291549.3		c.*774T>C		3_prime_UTR	Exon 4 of 4	NP_001278478.1
	CDKN1A	NM_001374509.1		c.*774T>C		3_prime_UTR	Exon 4 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.*774T>C		3_prime_UTR	Exon 3 of 3	ENSP00000244741.6
	CDKN1A	ENST00000405375.5	TSL:1	c.*774T>C		3_prime_UTR	Exon 3 of 3	ENSP00000384849.1
	CDKN1A	ENST00000373711.4	TSL:5	c.*774T>C		3_prime_UTR	Exon 4 of 4	ENSP00000362815.1

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

African (AFR) AF: 0.995 AC: 3889 AN: 3908

American (AMR) AF: 0.990 AC: 2476 AN: 2502

Ashkenazi Jewish (ASJ) AF: 0.976 AC: 5009 AN: 5130

East Asian (EAS) AF: 1.00 AC: 11410 AN: 11414

South Asian (SAS) AF: 0.964 AC: 688 AN: 714

European-Finnish (FIN) AF: 0.978 AC: 452 AN: 462

Middle Eastern (MID) AF: 0.986 AC: 493 AN: 500

European-Non Finnish (NFE) AF: 0.975 AC: 49002 AN: 50282

Other (OTH) AF: 0.984 AC: 6690 AN: 6800

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

African (AFR) AF: 0.995 AC: 41330 AN: 41536

American (AMR) AF: 0.984 AC: 15051 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.978 AC: 3395 AN: 3472

East Asian (EAS) AF: 0.998 AC: 5152 AN: 5160

South Asian (SAS) AF: 0.962 AC: 4641 AN: 4822

European-Finnish (FIN) AF: 0.971 AC: 10303 AN: 10612

Middle Eastern (MID) AF: 0.983 AC: 289 AN: 294

European-Non Finnish (NFE) AF: 0.974 AC: 66223 AN: 68012

Other (OTH) AF: 0.977 AC: 2068 AN: 2116

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.9
DANN	Benign	0.48
PhyloP100		-0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6457937; hg19: chr6-36654351;