rs3176343

Variant names:

• chr6-36682490-G-A
• rs3176343
• NM_000389.5:c.-5-1607G>A

Variant summary

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

The NM_000389.5(CDKN1A):​c.-5-1607G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0884 in 152,264 control chromosomes in the GnomAD database, including 819 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 0.088 (819 hom., cov: 32)
  • Exomes 𝑓: 0.058 (0 hom.)
• Consequence: CDKN1A NM_000389.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0600
• Publications: 14 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=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.282 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000389.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1A	NM_000389.5	MANE Select	c.-5-1607G>A		intron	N/A	NP_000380.1	P38936
	CDKN1A	NM_001291549.3		c.98-1607G>A		intron	N/A	NP_001278478.1
	CDKN1A	NM_001374509.1		c.98-1607G>A		intron	N/A	NP_001361438.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1A	ENST00000244741.10	TSL:1 MANE Select	c.-5-1607G>A		intron	N/A	ENSP00000244741.6	P38936
	CDKN1A	ENST00000405375.5	TSL:1	c.-5-1607G>A		intron	N/A	ENSP00000384849.1	P38936
	CDKN1A	ENST00000864207.1		c.-1612G>A		5_prime_UTR	Exon 1 of 2	ENSP00000534266.1

Frequencies

GnomAD3 genomes AF: 0.0885 AC: 13458 AN: 152094 Hom.: 825 Cov.: 32

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.0894

Gnomad ASJ AF: 0.0734

Gnomad EAS AF: 0.295

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.0339

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0524

Gnomad OTH AF: 0.0821

GnomAD4 exome AF: 0.0577 AC: 3 AN: 52 Hom.: 0 AF XY: 0.0476 AC XY: 2 AN XY: 42

African (AFR) AF: 0.500 AC: 1 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0556 AC: 2 AN: 36

Other (OTH) AF: 0.00 AC: 0 AN: 10

GnomAD4 genome AF: 0.0884 AC: 13460 AN: 152212 Hom.: 819 Cov.: 32 AF XY: 0.0902 AC XY: 6711 AN XY: 74430

African (AFR) AF: 0.136 AC: 5647 AN: 41508

American (AMR) AF: 0.0892 AC: 1364 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0734 AC: 255 AN: 3472

East Asian (EAS) AF: 0.294 AC: 1519 AN: 5170

South Asian (SAS) AF: 0.104 AC: 503 AN: 4818

European-Finnish (FIN) AF: 0.0339 AC: 360 AN: 10616

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0524 AC: 3564 AN: 68020

Other (OTH) AF: 0.0826 AC: 174 AN: 2106

Alfa AF: 0.0634 Hom.: 188

Bravo AF: 0.0956

Asia WGS AF: 0.160 AC: 557 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.8
DANN	Benign	0.54
PhyloP100		0.060
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: rs3176343; hg19: chr6-36650267;