6-36676733-A-G

Variant names:

• chr6-36676733-A-G
• rs3829965
• NM_001291549.3:c.-142+163A>G

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+163A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.218 in 151,930 control chromosomes in the GnomAD database, including 4,471 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 0.22 (4471 hom., cov: 32)
• Consequence: CDKN1A NM_001291549.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.392
• Publications: 5 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=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.407 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN1A	NM_001291549.3	c.-142+163A>G		intron_variant	Intron 1 of 3		NP_001278478.1
CDKN1A	NM_001374509.1	c.-50+163A>G		intron_variant	Intron 1 of 3		NP_001361438.1
CDKN1A	NM_001374510.1	c.34+163A>G		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+209A>G		intron_variant	Intron 1 of 3	3		ENSP00000409259.3
CDKN1A	ENST00000615513.4	c.-6+209A>G		intron_variant	Intron 1 of 2	2		ENSP00000482768.1
CDKN1A	ENST00000459970.1	n.43+163A>G		intron_variant	Intron 1 of 2	5

Frequencies

GnomAD3 genomes AF: 0.218 AC: 33127 AN: 151814 Hom.: 4456 Cov.: 32

Gnomad AFR AF: 0.330

Gnomad AMI AF: 0.143

Gnomad AMR AF: 0.322

Gnomad ASJ AF: 0.0956

Gnomad EAS AF: 0.423

Gnomad SAS AF: 0.122

Gnomad FIN AF: 0.119

Gnomad MID AF: 0.156

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.219

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

GnomAD4 genome AF: 0.218 AC: 33186 AN: 151930 Hom.: 4471 Cov.: 32 AF XY: 0.219 AC XY: 16266 AN XY: 74234

African (AFR) AF: 0.330 AC: 13654 AN: 41386

American (AMR) AF: 0.322 AC: 4925 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0956 AC: 332 AN: 3472

East Asian (EAS) AF: 0.422 AC: 2179 AN: 5164

South Asian (SAS) AF: 0.122 AC: 588 AN: 4818

European-Finnish (FIN) AF: 0.119 AC: 1252 AN: 10526

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.142 AC: 9621 AN: 67978

Other (OTH) AF: 0.218 AC: 459 AN: 2104

Alfa AF: 0.183 Hom.: 425

Bravo AF: 0.246

Asia WGS AF: 0.251 AC: 873 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	0.64
PhyloP100		-0.39
PromoterAI		-0.0018	Neutral

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: rs3829965; hg19: chr6-36644510;