rs3176326

Variant names:

• chr6-36679512-G-A
• rs3176326
• NM_000389.5:c.-6+714G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000389.5(CDKN1A):​c.-6+714G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.198 in 152,196 control chromosomes in the GnomAD database, including 2,984 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 0.20 (2984 hom., cov: 32)
• Consequence: CDKN1A NM_000389.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.563
• Publications: 37 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=-0.8).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.285 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN1A	NM_000389.5	c.-6+714G>A		intron_variant	Intron 1 of 2	ENST00000244741.10	NP_000380.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN1A	ENST00000244741.10	c.-6+714G>A		intron_variant	Intron 1 of 2	1	NM_000389.5	ENSP00000244741.6

Frequencies

GnomAD3 genomes AF: 0.198 AC: 30135 AN: 152078 Hom.: 2979 Cov.: 32

Gnomad AFR AF: 0.196

Gnomad AMI AF: 0.0669

Gnomad AMR AF: 0.182

Gnomad ASJ AF: 0.262

Gnomad EAS AF: 0.128

Gnomad SAS AF: 0.298

Gnomad FIN AF: 0.178

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.202

Gnomad OTH AF: 0.232

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.198 AC: 30156 AN: 152196 Hom.: 2984 Cov.: 32 AF XY: 0.197 AC XY: 14655 AN XY: 74408

African (AFR) AF: 0.195 AC: 8112 AN: 41538

American (AMR) AF: 0.181 AC: 2774 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.262 AC: 909 AN: 3468

East Asian (EAS) AF: 0.128 AC: 661 AN: 5174

South Asian (SAS) AF: 0.298 AC: 1436 AN: 4822

European-Finnish (FIN) AF: 0.178 AC: 1885 AN: 10598

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.202 AC: 13726 AN: 67984

Other (OTH) AF: 0.239 AC: 504 AN: 2108

Alfa AF: 0.208 Hom.: 934

Bravo AF: 0.194

Asia WGS AF: 0.252 AC: 878 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.7
DANN	Benign	0.78
PhyloP100		-0.56
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: rs3176326; hg19: chr6-36647289;