Genetic Variant MKI67:p.Lys3217Glu (chr10-128101314-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002417.5(MKI67):c.9649A>G(p.Lys3217Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.514 in 1,613,866 control chromosomes in the GnomAD database, including 214,248 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.50 ( 19138 hom., cov: 34)

Exomes 𝑓: 0.52 ( 195110 hom. )

Consequence

MKI67
NM_002417.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.513

Publications

40 publications found

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 was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.121955E-6).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.548 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MKI67	NM_002417.5 link	c.9649A>G	p.Lys3217Glu	missense_variant	Exon 14 of 15	ENST00000368654.8	NP_002408.3	P46013-1
MKI67	NM_001145966.2 link	c.8569A>G	p.Lys2857Glu	missense_variant	Exon 13 of 14		NP_001139438.1	P46013-2
MKI67	XM_011539818.3 link	c.8617A>G	p.Lys2873Glu	missense_variant	Exon 11 of 12		XP_011538120.1
MKI67	XM_006717864.4 link	c.7327A>G	p.Lys2443Glu	missense_variant	Exon 3 of 4		XP_006717927.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MKI67	ENST00000368654.8 link	c.9649A>G	p.Lys3217Glu	missense_variant	Exon 14 of 15	2	NM_002417.5	ENSP00000357643.3	P46013-1
MKI67	ENST00000368653.7 link	c.8569A>G	p.Lys2857Glu	missense_variant	Exon 13 of 14	2		ENSP00000357642.3	P46013-2
MKI67	ENST00000464771.1 link	n.*170A>G		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.500

AC:

75960

AN:

152020

Hom.:

19137

Cov.:

show subpopulations

Gnomad AFR

AF:

0.466

Gnomad AMI

AF:

0.670

Gnomad AMR

AF:

0.559

Gnomad ASJ

AF:

0.573

Gnomad EAS

AF:

0.402

Gnomad SAS

AF:

0.408

Gnomad FIN

AF:

0.477

Gnomad MID

AF:

0.528

Gnomad NFE

AF:

0.518

Gnomad OTH

AF:

0.524

GnomAD2 exomes

AF:

0.508

AC:

127625

AN:

251464

AF XY:

0.502

show subpopulations

Gnomad AFR exome

AF:

0.459

Gnomad AMR exome

AF:

0.597

Gnomad ASJ exome

AF:

0.585

Gnomad EAS exome

AF:

0.407

Gnomad FIN exome

AF:

0.478

Gnomad NFE exome

AF:

0.525

Gnomad OTH exome

AF:

0.525

GnomAD4 exome

AF:

0.515

AC:

753278

AN:

1461728

Hom.:

195110

Cov.:

AF XY:

0.512

AC XY:

372613

AN XY:

727158

show subpopulations

African (AFR)

AF:

0.455

AC:

15242

AN:

33480

American (AMR)

AF:

0.595

AC:

26594

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.576

AC:

15063

AN:

26132

East Asian (EAS)

AF:

0.443

AC:

17600

AN:

39700

South Asian (SAS)

AF:

0.421

AC:

36285

AN:

86254

European-Finnish (FIN)

AF:

0.486

AC:

25979

AN:

53406

Middle Eastern (MID)

AF:

0.518

AC:

2986

AN:

5768

European-Non Finnish (NFE)

AF:

0.524

AC:

582984

AN:

1111874

Other (OTH)

AF:

0.506

AC:

30545

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

21331

42662

63992

85323

106654

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16744

33488

50232

66976

83720

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.499

AC:

75988

AN:

152138

Hom.:

19138

Cov.:

AF XY:

0.498

AC XY:

37012

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.465

AC:

19318

AN:

41500

American (AMR)

AF:

0.558

AC:

8543

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.573

AC:

1987

AN:

3470

East Asian (EAS)

AF:

0.402

AC:

2079

AN:

5174

South Asian (SAS)

AF:

0.406

AC:

1958

AN:

4822

European-Finnish (FIN)

AF:

0.477

AC:

5041

AN:

10572

Middle Eastern (MID)

AF:

0.537

AC:

158

AN:

294

European-Non Finnish (NFE)

AF:

0.518

AC:

35192

AN:

67988

Other (OTH)

AF:

0.523

AC:

1101

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

2016

4033

6049

8066

10082

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

674

1348

2022

2696

3370

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.520

Hom.:

71846

Bravo

AF:

0.509

TwinsUK

AF:

0.518

AC:

1920

ALSPAC

AF:

0.537

AC:

2070

ESP6500AA

AF:

0.464

AC:

2045

ESP6500EA

AF:

0.525

AC:

4511

ExAC

AF:

0.501

AC:

60891

Asia WGS

AF:

0.433

AC:

1507

AN:

3478

EpiCase

AF:

0.526

EpiControl

AF:

0.528

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.051

BayesDel_addAF

Benign

-0.85

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.36

(source)

DANN

Benign

0.12

DEOGEN2

Benign

0.0028

.;T

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0069

LIST_S2

Benign

0.27

T;T

MetaRNN

Benign

0.0000081

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.34

.;N

PhyloP100

-0.51

PrimateAI

Benign

0.25

PROVEAN

Benign

1.1

N;N

REVEL

Benign

0.018

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;B

Vest4

0.039

MPC

0.052

ClinPred

0.0049

GERP RS

-1.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.043

gMVP

0.013

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over