chr12-12720367-G-A

Variant names:

• chr12-12720367-G-A
• rs3093736
• NM_004064.5:c.*9-669G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_004064.5(CDKN1B):​c.*9-669G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0228 in 152,236 control chromosomes in the GnomAD database, including 59 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 0.023 (59 hom., cov: 32)
• Consequence: CDKN1B NM_004064.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.130
• Publications: 11 publications found

Genes affected

CDKN1B (HGNC:1785): (cyclin dependent kinase inhibitor 1B) This gene encodes a cyclin-dependent kinase inhibitor, which shares a limited similarity with CDK inhibitor CDKN1A/p21. The encoded protein binds to and prevents the activation of cyclin E-CDK2 or cyclin D-CDK4 complexes, and thus controls the cell cycle progression at G1. The degradation of this protein, which is triggered by its CDK dependent phosphorylation and subsequent ubiquitination by SCF complexes, is required for the cellular transition from quiescence to the proliferative state. Mutations in this gene are associated with multiple endocrine neoplasia type IV (MEN4). [provided by RefSeq, Apr 2014]

CDKN1B Gene-Disease associations (from GenCC):

• multiple endocrine neoplasia type 4

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, ClinGen
• multiple endocrine neoplasia

  Inheritance: AD Classification: STRONG Submitted by: G2P
• hereditary nonpolyposis colon cancer

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0228 (3466/152236) while in subpopulation NFE AF = 0.0319 (2170/68006). AF 95% confidence interval is 0.0308. There are 59 homozygotes in GnomAd4. There are 1729 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 59 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004064.5. 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
	CDKN1B	NM_004064.5	MANE Select	c.*9-669G>A		intron	N/A	NP_004055.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1B	ENST00000228872.9	TSL:1 MANE Select	c.*9-669G>A		intron	N/A	ENSP00000228872.4
	CDKN1B	ENST00000614874.2	TSL:6	c.*1421G>A		3_prime_UTR	Exon 2 of 2	ENSP00000507272.1
	CDKN1B	ENST00000396340.1	TSL:3	c.476-698G>A		intron	N/A	ENSP00000379629.1

Frequencies

GnomAD3 genomes AF: 0.0228 AC: 3466 AN: 152118 Hom.: 59 Cov.: 32

Gnomad AFR AF: 0.00521

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.00943

Gnomad ASJ AF: 0.0291

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00765

Gnomad FIN AF: 0.0700

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0319

Gnomad OTH AF: 0.0168

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

GnomAD4 genome AF: 0.0228 AC: 3466 AN: 152236 Hom.: 59 Cov.: 32 AF XY: 0.0232 AC XY: 1729 AN XY: 74426

African (AFR) AF: 0.00520 AC: 216 AN: 41548

American (AMR) AF: 0.00942 AC: 144 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0291 AC: 101 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.00786 AC: 38 AN: 4834

European-Finnish (FIN) AF: 0.0700 AC: 740 AN: 10578

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0319 AC: 2170 AN: 68006

Other (OTH) AF: 0.0166 AC: 35 AN: 2110

Alfa AF: 0.0291 Hom.: 43

Bravo AF: 0.0179

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.0
DANN	Benign	0.28
PhyloP100		-0.13
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: rs3093736; hg19: chr12-12873301;