rs3176344

Positions:

• chr6-36682770-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000389.5(CDKN1A):​c.-5-1327G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.029 in 152,348 control chromosomes in the GnomAD database, including 80 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 0.029 (80 hom., cov: 32)
  • Exomes 𝑓: 0.024 (0 hom.)
• Consequence: CDKN1A NM_000389.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.357

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.029 (4420/152306) while in subpopulation AMR AF= 0.0442 (676/15300). AF 95% confidence interval is 0.0414. There are 80 homozygotes in gnomad4. There are 2150 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 4420 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN1A	NM_000389.5	c.-5-1327G>A		intron_variant		ENST00000244741.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN1A	ENST00000244741.10	c.-5-1327G>A		intron_variant		1	NM_000389.5	P1

Frequencies

GnomAD3 genomes AF: 0.0290 AC: 4421 AN: 152188 Hom.: 80 Cov.: 32

Gnomad AFR AF: 0.00736

Gnomad AMI AF: 0.0943

Gnomad AMR AF: 0.0442

Gnomad ASJ AF: 0.0421

Gnomad EAS AF: 0.00481

Gnomad SAS AF: 0.00849

Gnomad FIN AF: 0.0472

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0374

Gnomad OTH AF: 0.0430

GnomAD4 exome AF: 0.0238 AC: 1 AN: 42 Hom.: 0 Cov.: 0 AF XY: 0.0333 AC XY: 1 AN XY: 30

Gnomad4 AFR exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0313

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0290 AC: 4420 AN: 152306 Hom.: 80 Cov.: 32 AF XY: 0.0289 AC XY: 2150 AN XY: 74474

Gnomad4 AFR AF: 0.00734

Gnomad4 AMR AF: 0.0442

Gnomad4 ASJ AF: 0.0421

Gnomad4 EAS AF: 0.00502

Gnomad4 SAS AF: 0.00849

Gnomad4 FIN AF: 0.0472

Gnomad4 NFE AF: 0.0374

Gnomad4 OTH AF: 0.0426

Alfa AF: 0.0366 Hom.: 23

Bravo AF: 0.0289

Asia WGS AF: 0.00924 AC: 32 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	5.9
DANN	Benign	0.61

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

Publications

LitVar

Other links and lift over

dbSNP: rs3176344; hg19: chr6-36650547;