6-36684112-C-T

Position:

chr6-36684112-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_000389.5(CDKN1A):c.11C>T(p.Pro4Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000962 in 1,613,390 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.0056 ( 11 hom., cov: 32)

Exomes 𝑓: 0.00048 ( 6 hom. )

Consequence

CDKN1A
NM_000389.5 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.14

Variant links:

Genes affected

CDKN1A (HGNC:1784): (cyclin dependent kinase inhibitor 1A) This gene encodes a potent cyclin-dependent kinase inhibitor. The encoded protein binds to and inhibits the activity of cyclin-cyclin-dependent kinase2 or -cyclin-dependent kinase4 complexes, and thus functions as a regulator of cell cycle progression at G1. The expression of this gene is tightly controlled by the tumor suppressor protein p53, through which this protein mediates the p53-dependent cell cycle G1 phase arrest in response to a variety of stress stimuli. This protein can interact with proliferating cell nuclear antigen, a DNA polymerase accessory factor, and plays a regulatory role in S phase DNA replication and DNA damage repair. This protein was reported to be specifically cleaved by CASP3-like caspases, which thus leads to a dramatic activation of cyclin-dependent kinase2, and may be instrumental in the execution of apoptosis following caspase activation. Mice that lack this gene have the ability to regenerate damaged or missing tissue. Multiple alternatively spliced variants have been found for this gene. [provided by RefSeq, Sep 2015]

CDKN1A links:

CDKN1A (HGNC:):

CDKN1A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0025286973).

BP6

Variant 6-36684112-C-T is Benign according to our data. Variant chr6-36684112-C-T is described in ClinVar as [Benign]. Clinvar id is 773195.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-36684112-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0056 (853/152340) while in subpopulation AFR AF= 0.0196 (813/41582). AF 95% confidence interval is 0.0184. There are 11 homozygotes in gnomad4. There are 391 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 853 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN1A	NM_000389.5 linkuse as main transcript	c.11C>T	p.Pro4Leu	missense_variant	2/3	ENST00000244741.10	NP_000380.1	P38936A0A024RCX5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKN1A	ENST00000244741.10 linkuse as main transcript	c.11C>T	p.Pro4Leu	missense_variant	2/3	1	NM_000389.5	ENSP00000244741.6		P38936

Frequencies

GnomAD3 genomes

AF:

0.00556

AC:

847

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0195

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00190

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00138

AC:

345

AN:

249842

Hom.:

AF XY:

0.00105

AC XY:

142

AN XY:

135366

show subpopulations

Gnomad AFR exome

AF:

0.0196

Gnomad AMR exome

AF:

0.000782

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000478

AC:

699

AN:

1461050

Hom.:

Cov.:

AF XY:

0.000421

AC XY:

306

AN XY:

726866

show subpopulations

Gnomad4 AFR exome

AF:

0.0176

Gnomad4 AMR exome

AF:

0.000850

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.000795

GnomAD4 genome

AF:

0.00560

AC:

853

AN:

152340

Hom.:

Cov.:

AF XY:

0.00525

AC XY:

391

AN XY:

74510

show subpopulations

Gnomad4 AFR

AF:

0.0196

Gnomad4 AMR

AF:

0.00189

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.000800

Hom.:

Bravo

AF:

0.00602

ESP6500AA

AF:

0.0207

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00173

AC:

210

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 29, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.52

CADD

Benign

8.7

DANN

Benign

0.84

DEOGEN2

Benign

0.068

T;T;T;T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.34

.;T;.;.;.

MetaRNN

Benign

0.0025

T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.3

M;M;M;M;M

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.010

.;.;N;N;N

REVEL

Benign

0.14

Sift

Benign

0.066

.;.;T;T;T

Sift4G

Uncertain

0.025

D;D;D;D;D

Polyphen

0.0020

B;B;B;B;B

Vest4

0.095

MVP

0.71

MPC

0.17

ClinPred

0.0042

GERP RS

-4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.029

gMVP

0.29

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over