rs137985549

Variant names:

• chr12-12718236-C-A
• rs137985549
• NM_004064.5:c.397C>A

Your query was ambiguous. Multiple possible variants found:

• chr12-12718236-C-A
• chr12-12718236-C-G
• chr12-12718236-C-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004064.5(CDKN1B):​c.397C>A​(p.Pro133Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000239 in 1,612,200 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P133S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00024 (4 hom.)
• Consequence: CDKN1B NM_004064.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:8
• Conservation: PhyloP100: 2.39
• Publications: 18 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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• multiple endocrine neoplasia

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

  Inheritance: Unknown Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006507486).
• BP6: Variant 12-12718236-C-A is Benign according to our data. Variant chr12-12718236-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 217127.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00021 (32/152306) while in subpopulation AMR AF = 0.000457 (7/15306). AF 95% confidence interval is 0.000215. There are 0 homozygotes in GnomAd4. There are 16 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1B	NM_004064.5	MANE Select	c.397C>A	p.Pro133Thr	missense	Exon 1 of 3	NP_004055.1	Q6I9V6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1B	ENST00000228872.9	TSL:1 MANE Select	c.397C>A	p.Pro133Thr	missense	Exon 1 of 3	ENSP00000228872.4	P46527
	CDKN1B	ENST00000396340.1	TSL:3	c.397C>A	p.Pro133Thr	missense	Exon 1 of 2	ENSP00000379629.1	E7ES52
	CDKN1B	ENST00000614874.2	TSL:6	c.397C>A	p.Pro133Thr	missense	Exon 1 of 2	ENSP00000507272.1	P46527

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152188 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000408 AC: 101 AN: 247586 AF XY: 0.000447

Gnomad AFR exome AF: 0.0000630

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00340

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000499

Gnomad NFE exome AF: 0.000222

Gnomad OTH exome AF: 0.000494

GnomAD4 exome AF: 0.000242 AC: 353 AN: 1459894 Hom.: 4 Cov.: 38 AF XY: 0.000264 AC XY: 192 AN XY: 726296

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.000246 AC: 11 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00371 AC: 97 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000672 AC: 58 AN: 86256

European-Finnish (FIN) AF: 0.0000194 AC: 1 AN: 51464

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.000129 AC: 143 AN: 1111992

Other (OTH) AF: 0.000480 AC: 29 AN: 60382

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152306 Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16 AN XY: 74478

African (AFR) AF: 0.0000481 AC: 2 AN: 41558

American (AMR) AF: 0.000457 AC: 7 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68024

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000290 Hom.: 2

Bravo AF: 0.000170

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000511 AC: 62

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	Multiple endocrine neoplasia type 4 (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	1	1	not specified (2)
-	-	1	CDKN1B-related disorder (1)
-	-	1	not provided (1)
-	1	-	Primary hyperparathyroidism (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.0065	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		2.4
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.26
Sift	Benign	0.20	T
Sift4G	Benign	0.53	T
Polyphen		0.0020	B
Vest4		0.044
MVP		0.85
MPC		0.077
ClinPred		0.013	T
GERP RS		5.3
PromoterAI		0.0065	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.088
gMVP		0.20
Mutation Taster		=87/13	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: rs137985549; hg19: chr12-12871170; COSMIC: COSV99963856;