NM_004064.5:c.326T>G

Variant names:

• chr12-12718165-T-G
• rs2066827
• NM_004064.5:c.326T>G

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.326T>G​(p.Val109Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 1,613,296 control chromosomes in the GnomAD database, including 64,983 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V109A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.37 (14114 hom., cov: 33)
  • Exomes 𝑓: 0.25 (50869 hom.)
• Consequence: CDKN1B NM_004064.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.19
• Publications: 164 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.5013622E-6).
• BP6: Variant 12-12718165-T-G is Benign according to our data. Variant chr12-12718165-T-G is described in ClinVar as Benign. ClinVar VariationId is 259226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.709 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.326T>G	p.Val109Gly	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.326T>G	p.Val109Gly	missense	Exon 1 of 3	ENSP00000228872.4	P46527
	CDKN1B	ENST00000396340.1	TSL:3	c.326T>G	p.Val109Gly	missense	Exon 1 of 2	ENSP00000379629.1	E7ES52
	CDKN1B	ENST00000614874.2	TSL:6	c.326T>G	p.Val109Gly	missense	Exon 1 of 2	ENSP00000507272.1	P46527

Frequencies

GnomAD3 genomes AF: 0.370 AC: 56202 AN: 152090 Hom.: 14093 Cov.: 33

Gnomad AFR AF: 0.716

Gnomad AMI AF: 0.0910

Gnomad AMR AF: 0.256

Gnomad ASJ AF: 0.267

Gnomad EAS AF: 0.0451

Gnomad SAS AF: 0.316

Gnomad FIN AF: 0.253

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.240

Gnomad OTH AF: 0.347

GnomAD2 exomes AF: 0.259 AC: 64341 AN: 248658 AF XY: 0.261

Gnomad AFR exome AF: 0.726

Gnomad AMR exome AF: 0.153

Gnomad ASJ exome AF: 0.260

Gnomad EAS exome AF: 0.0383

Gnomad FIN exome AF: 0.253

Gnomad NFE exome AF: 0.248

Gnomad OTH exome AF: 0.272

GnomAD4 exome AF: 0.247 AC: 360349 AN: 1461088 Hom.: 50869 Cov.: 59 AF XY: 0.248 AC XY: 180218 AN XY: 726816

African (AFR) AF: 0.737 AC: 24653 AN: 33444

American (AMR) AF: 0.165 AC: 7394 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.251 AC: 6567 AN: 26126

East Asian (EAS) AF: 0.0322 AC: 1277 AN: 39694

South Asian (SAS) AF: 0.310 AC: 26731 AN: 86242

European-Finnish (FIN) AF: 0.250 AC: 13277 AN: 53054

Middle Eastern (MID) AF: 0.374 AC: 2141 AN: 5728

European-Non Finnish (NFE) AF: 0.236 AC: 262031 AN: 1111750

Other (OTH) AF: 0.270 AC: 16278 AN: 60360

GnomAD4 genome AF: 0.370 AC: 56265 AN: 152208 Hom.: 14114 Cov.: 33 AF XY: 0.366 AC XY: 27242 AN XY: 74436

African (AFR) AF: 0.716 AC: 29730 AN: 41520

American (AMR) AF: 0.255 AC: 3901 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.267 AC: 925 AN: 3468

East Asian (EAS) AF: 0.0455 AC: 236 AN: 5182

South Asian (SAS) AF: 0.316 AC: 1525 AN: 4830

European-Finnish (FIN) AF: 0.253 AC: 2683 AN: 10610

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

European-Non Finnish (NFE) AF: 0.240 AC: 16335 AN: 67990

Other (OTH) AF: 0.342 AC: 724 AN: 2116

Alfa AF: 0.264 Hom.: 21394

Bravo AF: 0.380

TwinsUK AF: 0.204 AC: 755

ALSPAC AF: 0.233 AC: 899

ESP6500AA AF: 0.693 AC: 3047

ESP6500EA AF: 0.238 AC: 2044

ExAC AF: 0.274 AC: 33233

Asia WGS AF: 0.231 AC: 804 AN: 3478

EpiCase AF: 0.250

EpiControl AF: 0.258

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Multiple endocrine neoplasia type 4 (4)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	17
DANN	Benign	0.92
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.31	T
MetaRNN	Benign	0.0000015	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.7	L
PhyloP100		1.2
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.078
Sift	Benign	0.22	T
Sift4G	Benign	0.23	T
Polyphen		0.047	B
Vest4		0.13
MPC		0.089
ClinPred		0.0031	T
GERP RS		-0.90
PromoterAI		0.032	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.16
gMVP		0.42
Mutation Taster		=97/3	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: rs2066827; hg19: chr12-12871099; COSMIC: COSV57429460; COSMIC: COSV57429460;