12-12717761-T-C

Variant names:

• chr12-12717761-T-C
• rs34330
• NM_004064.5:c.-79T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004064.5(CDKN1B):​c.-79T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.744 in 1,599,978 control chromosomes in the GnomAD database, including 445,453 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (38094 hom., cov: 34)
  • Exomes 𝑓: 0.75 (407359 hom.)
• Consequence: CDKN1B NM_004064.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.109
• Publications: 94 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 12-12717761-T-C is Benign according to our data. Variant chr12-12717761-T-C is described in ClinVar as Benign. ClinVar VariationId is 307658.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.761 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1B	NM_004064.5	MANE Select	c.-79T>C		5_prime_UTR	Exon 1 of 3	NP_004055.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1B	ENST00000228872.9	TSL:1 MANE Select	c.-79T>C		5_prime_UTR	Exon 1 of 3	ENSP00000228872.4
	CDKN1B	ENST00000614874.2	TSL:6	c.-79T>C		5_prime_UTR	Exon 1 of 2	ENSP00000507272.1
	CDKN1B	ENST00000907758.1		c.-79T>C		5_prime_UTR	Exon 1 of 3	ENSP00000577817.1

Frequencies

GnomAD3 genomes AF: 0.701 AC: 106549 AN: 152040 Hom.: 38072 Cov.: 34

Gnomad AFR AF: 0.567

Gnomad AMI AF: 0.687

Gnomad AMR AF: 0.763

Gnomad ASJ AF: 0.854

Gnomad EAS AF: 0.513

Gnomad SAS AF: 0.782

Gnomad FIN AF: 0.779

Gnomad MID AF: 0.712

Gnomad NFE AF: 0.757

Gnomad OTH AF: 0.709

GnomAD4 exome AF: 0.748 AC: 1083132 AN: 1447820 Hom.: 407359 Cov.: 73 AF XY: 0.750 AC XY: 539979 AN XY: 720408

African (AFR) AF: 0.568 AC: 18968 AN: 33366

American (AMR) AF: 0.804 AC: 35629 AN: 44322

Ashkenazi Jewish (ASJ) AF: 0.849 AC: 22159 AN: 26110

East Asian (EAS) AF: 0.533 AC: 21125 AN: 39598

South Asian (SAS) AF: 0.786 AC: 67435 AN: 85834

European-Finnish (FIN) AF: 0.773 AC: 33699 AN: 43580

Middle Eastern (MID) AF: 0.793 AC: 3277 AN: 4130

European-Non Finnish (NFE) AF: 0.753 AC: 836421 AN: 1110836

Other (OTH) AF: 0.740 AC: 44419 AN: 60044

GnomAD4 genome AF: 0.701 AC: 106625 AN: 152158 Hom.: 38094 Cov.: 34 AF XY: 0.705 AC XY: 52458 AN XY: 74380

African (AFR) AF: 0.567 AC: 23524 AN: 41508

American (AMR) AF: 0.764 AC: 11675 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.854 AC: 2965 AN: 3472

East Asian (EAS) AF: 0.514 AC: 2647 AN: 5150

South Asian (SAS) AF: 0.781 AC: 3776 AN: 4832

European-Finnish (FIN) AF: 0.779 AC: 8253 AN: 10598

Middle Eastern (MID) AF: 0.711 AC: 209 AN: 294

European-Non Finnish (NFE) AF: 0.757 AC: 51460 AN: 67996

Other (OTH) AF: 0.707 AC: 1494 AN: 2114

Alfa AF: 0.738 Hom.: 123390

Bravo AF: 0.694

Asia WGS AF: 0.650 AC: 2265 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Multiple endocrine neoplasia type 4 (5)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	14
DANN	Benign	0.92
PhyloP100		-0.11
PromoterAI		-0.00060	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	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: rs34330; hg19: chr12-12870695; COSMIC: COSV57430533; COSMIC: COSV57430533;