NM_000389.5:c.-6+2241A>T

Variant names:

• chr6-36681039-A-T
• rs3176336
• NM_000389.5:c.-6+2241A>T

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+2241A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.54 in 151,932 control chromosomes in the GnomAD database, including 24,482 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 0.54 (24482 hom., cov: 31)
• Consequence: CDKN1A NM_000389.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.479
• Publications: 23 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=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.78 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN1A	NM_000389.5	c.-6+2241A>T		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+2241A>T		intron_variant	Intron 1 of 2	1	NM_000389.5	ENSP00000244741.6

Frequencies

GnomAD3 genomes AF: 0.540 AC: 81956 AN: 151816 Hom.: 24415 Cov.: 31

Gnomad AFR AF: 0.786

Gnomad AMI AF: 0.331

Gnomad AMR AF: 0.583

Gnomad ASJ AF: 0.551

Gnomad EAS AF: 0.723

Gnomad SAS AF: 0.470

Gnomad FIN AF: 0.386

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.397

Gnomad OTH AF: 0.557

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

GnomAD4 genome AF: 0.540 AC: 82085 AN: 151932 Hom.: 24482 Cov.: 31 AF XY: 0.543 AC XY: 40311 AN XY: 74230

African (AFR) AF: 0.787 AC: 32622 AN: 41450

American (AMR) AF: 0.584 AC: 8914 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.551 AC: 1910 AN: 3468

East Asian (EAS) AF: 0.722 AC: 3728 AN: 5160

South Asian (SAS) AF: 0.469 AC: 2251 AN: 4804

European-Finnish (FIN) AF: 0.386 AC: 4068 AN: 10528

Middle Eastern (MID) AF: 0.558 AC: 164 AN: 294

European-Non Finnish (NFE) AF: 0.397 AC: 26940 AN: 67934

Other (OTH) AF: 0.563 AC: 1187 AN: 2108

Alfa AF: 0.477 Hom.: 2515

Bravo AF: 0.570

Asia WGS AF: 0.611 AC: 2125 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	2.6
DANN	Benign	0.69
PhyloP100		-0.48
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: rs3176336; hg19: chr6-36648816;