6-36677426-T-C

Variant names:

• chr6-36677426-T-C
• rs733590
• NM_001291549.3:c.-141-270T>C

Variant summary

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

The NM_001291549.3(CDKN1A):​c.-141-270T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.411 in 151,954 control chromosomes in the GnomAD database, including 13,635 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 0.41 (13635 hom., cov: 32)
• Consequence: CDKN1A NM_001291549.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.318
• Publications: 39 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]

DINOL (HGNC:53146): (damage induced long noncoding RNA)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.546 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN1A	NM_001291549.3	c.-141-270T>C		intron_variant	Intron 1 of 3		NP_001278478.1
CDKN1A	NM_001374509.1	c.-49-362T>C		intron_variant	Intron 1 of 3		NP_001361438.1
CDKN1A	NM_001374510.1	c.34+856T>C		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.-37-476T>C		intron_variant	Intron 1 of 3	3		ENSP00000409259.3
CDKN1A	ENST00000615513.4	c.-6+902T>C		intron_variant	Intron 1 of 2	2		ENSP00000482768.1
CDKN1A	ENST00000459970.1	n.44-362T>C		intron_variant	Intron 1 of 2	5

Frequencies

GnomAD3 genomes AF: 0.411 AC: 62414 AN: 151836 Hom.: 13592 Cov.: 32

Gnomad AFR AF: 0.551

Gnomad AMI AF: 0.218

Gnomad AMR AF: 0.362

Gnomad ASJ AF: 0.527

Gnomad EAS AF: 0.288

Gnomad SAS AF: 0.373

Gnomad FIN AF: 0.329

Gnomad MID AF: 0.519

Gnomad NFE AF: 0.357

Gnomad OTH AF: 0.447

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

GnomAD4 genome AF: 0.411 AC: 62507 AN: 151954 Hom.: 13635 Cov.: 32 AF XY: 0.409 AC XY: 30415 AN XY: 74278

African (AFR) AF: 0.552 AC: 22853 AN: 41420

American (AMR) AF: 0.362 AC: 5526 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.527 AC: 1828 AN: 3466

East Asian (EAS) AF: 0.289 AC: 1493 AN: 5170

South Asian (SAS) AF: 0.372 AC: 1796 AN: 4824

European-Finnish (FIN) AF: 0.329 AC: 3461 AN: 10528

Middle Eastern (MID) AF: 0.524 AC: 154 AN: 294

European-Non Finnish (NFE) AF: 0.357 AC: 24244 AN: 67960

Other (OTH) AF: 0.453 AC: 953 AN: 2106

Alfa AF: 0.383 Hom.: 5818

Bravo AF: 0.419

Asia WGS AF: 0.374 AC: 1300 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.6
DANN	Benign	0.70
PhyloP100		-0.32

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: rs733590; hg19: chr6-36645203;