rs3829966

Variant names:

• chr6-36677174-C-T
• rs3829966
• NM_001291549.3:c.-141-522C>T

Variant summary

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

The NM_001291549.3(CDKN1A):​c.-141-522C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0794 in 152,096 control chromosomes in the GnomAD database, including 656 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 0.079 (656 hom., cov: 32)
• Consequence: CDKN1A NM_001291549.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.21
• Publications: 3 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=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN1A	NM_001291549.3	c.-141-522C>T		intron_variant	Intron 1 of 3		NP_001278478.1
CDKN1A	NM_001374509.1	c.-50+604C>T		intron_variant	Intron 1 of 3		NP_001361438.1
CDKN1A	NM_001374510.1	c.34+604C>T		intron_variant	Intron 1 of 2		NP_001361439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN1A	ENST00000448526.6	c.-38+650C>T		intron_variant	Intron 1 of 3	3		ENSP00000409259.3
CDKN1A	ENST00000615513.4	c.-6+650C>T		intron_variant	Intron 1 of 2	2		ENSP00000482768.1
CDKN1A	ENST00000459970.1	n.43+604C>T		intron_variant	Intron 1 of 2	5

Frequencies

GnomAD3 genomes AF: 0.0795 AC: 12075 AN: 151978 Hom.: 656 Cov.: 32

Gnomad AFR AF: 0.0169

Gnomad AMI AF: 0.0680

Gnomad AMR AF: 0.0846

Gnomad ASJ AF: 0.191

Gnomad EAS AF: 0.108

Gnomad SAS AF: 0.0500

Gnomad FIN AF: 0.137

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.101

Gnomad OTH AF: 0.0880

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

GnomAD4 genome AF: 0.0794 AC: 12072 AN: 152096 Hom.: 656 Cov.: 32 AF XY: 0.0833 AC XY: 6194 AN XY: 74334

African (AFR) AF: 0.0169 AC: 700 AN: 41506

American (AMR) AF: 0.0846 AC: 1292 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.191 AC: 664 AN: 3470

East Asian (EAS) AF: 0.108 AC: 560 AN: 5176

South Asian (SAS) AF: 0.0499 AC: 240 AN: 4814

European-Finnish (FIN) AF: 0.137 AC: 1447 AN: 10558

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.101 AC: 6887 AN: 67978

Other (OTH) AF: 0.0875 AC: 185 AN: 2114

Alfa AF: 0.0913 Hom.: 98

Bravo AF: 0.0742

Asia WGS AF: 0.0640 AC: 221 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.5
DANN	Benign	0.64
PhyloP100		-3.2

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: rs3829966; hg19: chr6-36644951;