6-36684562-C-G

Variant names:

• chr6-36684562-C-G
• rs3176352
• NM_000389.5:c.445+16C>G

Variant summary

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

The NM_000389.5(CDKN1A):​c.445+16C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.31 in 1,610,990 control chromosomes in the GnomAD database, including 87,473 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 0.40 (14215 hom., cov: 32)
  • Exomes 𝑓: 0.30 (73258 hom.)
• Consequence: CDKN1A NM_000389.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.00
• Publications: 34 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.623 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN1A	NM_000389.5	c.445+16C>G		intron_variant	Intron 2 of 2	ENST00000244741.10	NP_000380.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN1A	ENST00000244741.10	c.445+16C>G		intron_variant	Intron 2 of 2	1	NM_000389.5	ENSP00000244741.6

Frequencies

GnomAD3 genomes AF: 0.400 AC: 60710 AN: 151892 Hom.: 14168 Cov.: 32

Gnomad AFR AF: 0.629

Gnomad AMI AF: 0.289

Gnomad AMR AF: 0.433

Gnomad ASJ AF: 0.335

Gnomad EAS AF: 0.612

Gnomad SAS AF: 0.432

Gnomad FIN AF: 0.231

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.265

Gnomad OTH AF: 0.416

GnomAD2 exomes AF: 0.366 AC: 90909 AN: 248658 AF XY: 0.358

Gnomad AFR exome AF: 0.640

Gnomad AMR exome AF: 0.489

Gnomad ASJ exome AF: 0.352

Gnomad EAS exome AF: 0.596

Gnomad FIN exome AF: 0.228

Gnomad NFE exome AF: 0.267

Gnomad OTH exome AF: 0.335

GnomAD4 exome AF: 0.300 AC: 438142 AN: 1458980 Hom.: 73258 Cov.: 32 AF XY: 0.303 AC XY: 219932 AN XY: 725948

African (AFR) AF: 0.639 AC: 21388 AN: 33452

American (AMR) AF: 0.482 AC: 21513 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.351 AC: 9159 AN: 26118

East Asian (EAS) AF: 0.624 AC: 24741 AN: 39678

South Asian (SAS) AF: 0.418 AC: 35971 AN: 86156

European-Finnish (FIN) AF: 0.228 AC: 12118 AN: 53052

Middle Eastern (MID) AF: 0.417 AC: 2406 AN: 5764

European-Non Finnish (NFE) AF: 0.262 AC: 290355 AN: 1109786

Other (OTH) AF: 0.340 AC: 20491 AN: 60298

GnomAD4 genome AF: 0.400 AC: 60816 AN: 152010 Hom.: 14215 Cov.: 32 AF XY: 0.400 AC XY: 29711 AN XY: 74324

African (AFR) AF: 0.629 AC: 26069 AN: 41450

American (AMR) AF: 0.433 AC: 6626 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.335 AC: 1162 AN: 3464

East Asian (EAS) AF: 0.612 AC: 3143 AN: 5138

South Asian (SAS) AF: 0.431 AC: 2080 AN: 4826

European-Finnish (FIN) AF: 0.231 AC: 2451 AN: 10590

Middle Eastern (MID) AF: 0.418 AC: 123 AN: 294

European-Non Finnish (NFE) AF: 0.265 AC: 18005 AN: 67940

Other (OTH) AF: 0.423 AC: 893 AN: 2110

Alfa AF: 0.236 Hom.: 845

Bravo AF: 0.430

Asia WGS AF: 0.537 AC: 1865 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	12
DANN	Benign	0.64
PhyloP100		1.0
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: rs3176352; hg19: chr6-36652339; COSMIC: COSV55189067; COSMIC: COSV55189067;