12-12718246-A-G

Variant names:

• chr12-12718246-A-G
• rs546234840
• NM_004064.5:c.407A>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS1

The NM_004064.5(CDKN1B):​c.407A>G​(p.Asp136Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000119 in 1,611,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. D136N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: CDKN1B NM_004064.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:4
• Conservation: PhyloP100: 4.74
• Publications: 8 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.068461835).
• BP6: Variant 12-12718246-A-G is Benign according to our data. Variant chr12-12718246-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 307666.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000197 (30/152304) while in subpopulation AMR AF = 0.000915 (14/15302). AF 95% confidence interval is 0.000553. There are 0 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.407A>G	p.Asp136Gly	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.407A>G	p.Asp136Gly	missense	Exon 1 of 3	ENSP00000228872.4	P46527
	CDKN1B	ENST00000396340.1	TSL:3	c.407A>G	p.Asp136Gly	missense	Exon 1 of 2	ENSP00000379629.1	E7ES52
	CDKN1B	ENST00000614874.2	TSL:6	c.407A>G	p.Asp136Gly	missense	Exon 1 of 2	ENSP00000507272.1	P46527

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000689 AC: 17 AN: 246866 AF XY: 0.0000821

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000125

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000110 AC: 161 AN: 1459268 Hom.: 0 Cov.: 39 AF XY: 0.000112 AC XY: 81 AN XY: 726018

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000201 AC: 9 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

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

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50850

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.000121 AC: 134 AN: 1111984

Other (OTH) AF: 0.000215 AC: 13 AN: 60372

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152304 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74476

African (AFR) AF: 0.0000241 AC: 1 AN: 41570

American (AMR) AF: 0.000915 AC: 14 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68014

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000139 Hom.: 0

Bravo AF: 0.000223

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000990 AC: 12

EpiCase AF: 0.000382

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Benign	0.00059
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.068	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.8	L
PhyloP100		4.7
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.063
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.11	T
Polyphen		0.13	B
Vest4		0.30
MVP		0.54
MPC		0.14
ClinPred		0.13	T
GERP RS		5.3
PromoterAI		-0.054	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.29
Mutation Taster		=75/25	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: rs546234840; hg19: chr12-12871180; COSMIC: COSV57429693; COSMIC: COSV57429693;