Variant 10-128113592-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002417.5(MKI67):c.1491G>C(p.Glu497Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.185 in 1,613,010 control chromosomes in the GnomAD database, including 29,027 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.22 ( 4033 hom., cov: 33)

Exomes 𝑓: 0.18 ( 24994 hom. )

Consequence

MKI67
NM_002417.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.257

Variant links:

Genes affected

MKI67 (HGNC:7107): (marker of proliferation Ki-67) Enables protein C-terminus binding activity. Involved in regulation of chromosome segregation and regulation of mitotic nuclear division. Located in chromosome; nuclear body; and nucleolus. Colocalizes with condensed chromosome. Implicated in Crohn's disease; breast cancer; human immunodeficiency virus infectious disease; and pancreatic cancer. Biomarker of several diseases, including Barrett's esophagus; autoimmune disease of musculoskeletal system (multiple); endocrine gland cancer (multiple); gastrointestinal system cancer (multiple); and interstitial cystitis. [provided by Alliance of Genome Resources, Apr 2022]

MKI67 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0031678379).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.317 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MKI67	NM_002417.5 linkuse as main transcript	c.1491G>C	p.Glu497Asp	missense_variant	8/15	ENST00000368654.8	NP_002408.3
MKI67	NM_001145966.2 linkuse as main transcript	c.411G>C	p.Glu137Asp	missense_variant	7/14		NP_001139438.1
MKI67	XM_011539818.3 linkuse as main transcript	c.459G>C	p.Glu153Asp	missense_variant	5/12		XP_011538120.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MKI67	ENST00000368654.8 linkuse as main transcript	c.1491G>C	p.Glu497Asp	missense_variant	8/15	2	NM_002417.5	ENSP00000357643	P2	P46013-1
MKI67	ENST00000368653.7 linkuse as main transcript	c.411G>C	p.Glu137Asp	missense_variant	7/14	2		ENSP00000357642	A2	P46013-2

Frequencies

GnomAD3 genomes

AF:

0.220

AC:

33443

AN:

152046

Hom.:

4034

Cov.:

show subpopulations

Gnomad AFR

AF:

0.322

Gnomad AMI

AF:

0.264

Gnomad AMR

AF:

0.227

Gnomad ASJ

AF:

0.200

Gnomad EAS

AF:

0.269

Gnomad SAS

AF:

0.139

Gnomad FIN

AF:

0.123

Gnomad MID

AF:

0.184

Gnomad NFE

AF:

0.174

Gnomad OTH

AF:

0.213

GnomAD3 exomes

AF:

0.192

AC:

48207

AN:

251266

Hom.:

4919

AF XY:

0.184

AC XY:

25053

AN XY:

135812

show subpopulations

Gnomad AFR exome

AF:

0.323

Gnomad AMR exome

AF:

0.224

Gnomad ASJ exome

AF:

0.207

Gnomad EAS exome

AF:

0.285

Gnomad SAS exome

AF:

0.140

Gnomad FIN exome

AF:

0.127

Gnomad NFE exome

AF:

0.175

Gnomad OTH exome

AF:

0.169

GnomAD4 exome

AF:

0.182

AC:

265378

AN:

1460846

Hom.:

24994

Cov.:

AF XY:

0.180

AC XY:

130626

AN XY:

726778

show subpopulations

Gnomad4 AFR exome

AF:

0.320

Gnomad4 AMR exome

AF:

0.226

Gnomad4 ASJ exome

AF:

0.204

Gnomad4 EAS exome

AF:

0.274

Gnomad4 SAS exome

AF:

0.141

Gnomad4 FIN exome

AF:

0.125

Gnomad4 NFE exome

AF:

0.177

Gnomad4 OTH exome

AF:

0.190

GnomAD4 genome

AF:

0.220

AC:

33458

AN:

152164

Hom.:

4033

Cov.:

AF XY:

0.217

AC XY:

16171

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.322

Gnomad4 AMR

AF:

0.226

Gnomad4 ASJ

AF:

0.200

Gnomad4 EAS

AF:

0.268

Gnomad4 SAS

AF:

0.138

Gnomad4 FIN

AF:

0.123

Gnomad4 NFE

AF:

0.174

Gnomad4 OTH

AF:

0.213

Alfa

AF:

0.172

Hom.:

1790

Bravo

AF:

0.232

TwinsUK

AF:

0.176

AC:

654

ALSPAC

AF:

0.185

AC:

713

ESP6500AA

AF:

0.317

AC:

1395

ESP6500EA

AF:

0.176

AC:

1517

ExAC

AF:

0.190

AC:

23096

EpiCase

AF:

0.178

EpiControl

AF:

0.175

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.73

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.030

.;T

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.44

T;T

MetaRNN

Benign

0.0032

T;T

MetaSVM

Benign

-0.86

MutationAssessor

Uncertain

2.1

.;M

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.12

Sift

Uncertain

0.017

D;T

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.99

D;D

Vest4

0.027

MutPred

0.092

.;Loss of methylation at K502 (P = 0.1294);

MPC

0.057

ClinPred

0.020

GERP RS

0.71

Varity_R

0.070

gMVP

0.13

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

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over