rs3176344

Variant names:

• chr6-36682770-G-A
• rs3176344
• NM_000389.5:c.-5-1327G>A

Variant summary

Our verdict is Benign. The variant received -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
• 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=-0.8).
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4420 AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1A	NM_000389.5	MANE Select	c.-5-1327G>A		intron	N/A	NP_000380.1
	CDKN1A	NM_001291549.3		c.98-1327G>A		intron	N/A	NP_001278478.1
	CDKN1A	NM_001374509.1		c.98-1327G>A		intron	N/A	NP_001361438.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1A	ENST00000244741.10	TSL:1 MANE Select	c.-5-1327G>A		intron	N/A	ENSP00000244741.6
	CDKN1A	ENST00000405375.5	TSL:1	c.-5-1327G>A		intron	N/A	ENSP00000384849.1
	CDKN1A	ENST00000373711.4	TSL:5	c.-6+40G>A		intron	N/A	ENSP00000362815.1

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

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.0313 AC: 1 AN: 32

Other (OTH) AF: 0.00 AC: 0 AN: 4

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

African (AFR) AF: 0.00734 AC: 305 AN: 41570

American (AMR) AF: 0.0442 AC: 676 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0421 AC: 146 AN: 3470

East Asian (EAS) AF: 0.00502 AC: 26 AN: 5182

South Asian (SAS) AF: 0.00849 AC: 41 AN: 4828

European-Finnish (FIN) AF: 0.0472 AC: 501 AN: 10610

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0374 AC: 2541 AN: 68026

Other (OTH) AF: 0.0426 AC: 90 AN: 2114

Alfa AF: 0.0374 Hom.: 61

Bravo AF: 0.0289

Asia WGS AF: 0.00924 AC: 32 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	5.9
DANN	Benign	0.61
PhyloP100		0.36
Mutation Taster		=100/0	polymorphism

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: rs3176344; hg19: chr6-36650547;