rs4135237

Variant names:

• chr6-36677113-G-T
• rs4135237
• NM_001291549.3:c.-142+543G>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.-142+543G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0995 in 152,114 control chromosomes in the GnomAD database, including 844 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 0.099 (844 hom., cov: 32)
• Consequence: CDKN1A NM_001291549.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.101
• 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.-142+543G>T		intron_variant	Intron 1 of 3		NP_001278478.1
CDKN1A	NM_001374509.1	c.-50+543G>T		intron_variant	Intron 1 of 3		NP_001361438.1
CDKN1A	NM_001374510.1	c.34+543G>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+589G>T		intron_variant	Intron 1 of 3	3		ENSP00000409259.3
CDKN1A	ENST00000615513.4	c.-6+589G>T		intron_variant	Intron 1 of 2	2		ENSP00000482768.1
CDKN1A	ENST00000459970.1	n.43+543G>T		intron_variant	Intron 1 of 2	5

Frequencies

GnomAD3 genomes AF: 0.0995 AC: 15125 AN: 151996 Hom.: 844 Cov.: 32

Gnomad AFR AF: 0.0867

Gnomad AMI AF: 0.0680

Gnomad AMR AF: 0.0904

Gnomad ASJ AF: 0.191

Gnomad EAS AF: 0.108

Gnomad SAS AF: 0.0508

Gnomad FIN AF: 0.137

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.105

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

GnomAD4 genome AF: 0.0995 AC: 15134 AN: 152114 Hom.: 844 Cov.: 32 AF XY: 0.102 AC XY: 7595 AN XY: 74352

African (AFR) AF: 0.0868 AC: 3600 AN: 41486

American (AMR) AF: 0.0904 AC: 1382 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.191 AC: 662 AN: 3460

East Asian (EAS) AF: 0.108 AC: 560 AN: 5164

South Asian (SAS) AF: 0.0506 AC: 244 AN: 4822

European-Finnish (FIN) AF: 0.137 AC: 1445 AN: 10580

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

European-Non Finnish (NFE) AF: 0.102 AC: 6924 AN: 67996

Other (OTH) AF: 0.104 AC: 220 AN: 2110

Alfa AF: 0.103 Hom.: 129

Bravo AF: 0.0967

Asia WGS AF: 0.0680 AC: 235 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	11
DANN	Benign	0.76
PhyloP100		0.10

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4135237; hg19: chr6-36644890;