Genetic Variant NM_002417.5:c.8279A>G (chr10-128103561-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.8279A>G(p.Asp2760Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.183 in 1,613,804 control chromosomes in the GnomAD database, including 28,237 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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 0.22 ( 3891 hom., cov: 32)

Exomes 𝑓: 0.18 ( 24346 hom. )

Consequence

MKI67
NM_002417.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.363

Publications

21 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=0.0054243207).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.31 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
MKI67	NM_002417.5 link	c.8279A>G	p.Asp2760Gly	missense_variant	Exon 13 of 15	ENST00000368654.8	NP_002408.3
MKI67	NM_001145966.2 link	c.7199A>G	p.Asp2400Gly	missense_variant	Exon 12 of 14		NP_001139438.1
MKI67	XM_011539818.3 link	c.7247A>G	p.Asp2416Gly	missense_variant	Exon 10 of 12		XP_011538120.1
MKI67	XM_006717864.4 link	c.5957A>G	p.Asp1986Gly	missense_variant	Exon 2 of 4		XP_006717927.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MKI67	ENST00000368654.8 link	c.8279A>G	p.Asp2760Gly	missense_variant	Exon 13 of 15	2	NM_002417.5	ENSP00000357643.3
MKI67	ENST00000368653.7 link	c.7199A>G	p.Asp2400Gly	missense_variant	Exon 12 of 14	2		ENSP00000357642.3

Frequencies

GnomAD3 genomes

AF:

0.216

AC:

32865

AN:

151818

Hom.:

3892

Cov.:

show subpopulations

Gnomad AFR

AF:

0.314

Gnomad AMI

AF:

0.263

Gnomad AMR

AF:

0.226

Gnomad ASJ

AF:

0.200

Gnomad EAS

AF:

0.269

Gnomad SAS

AF:

0.139

Gnomad FIN

AF:

0.125

Gnomad MID

AF:

0.184

Gnomad NFE

AF:

0.171

Gnomad OTH

AF:

0.211

GnomAD2 exomes

AF:

0.190

AC:

47680

AN:

251194

AF XY:

0.183

show subpopulations

Gnomad AFR exome

AF:

0.315

Gnomad AMR exome

AF:

0.223

Gnomad ASJ exome

AF:

0.206

Gnomad EAS exome

AF:

0.286

Gnomad FIN exome

AF:

0.130

Gnomad NFE exome

AF:

0.171

Gnomad OTH exome

AF:

0.168

GnomAD4 exome

AF:

0.179

AC:

262280

AN:

1461868

Hom.:

24346

Cov.:

AF XY:

0.177

AC XY:

129011

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.313

AC:

10481

AN:

33478

American (AMR)

AF:

0.224

AC:

10034

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.204

AC:

5337

AN:

26136

East Asian (EAS)

AF:

0.275

AC:

10923

AN:

39700

South Asian (SAS)

AF:

0.141

AC:

12147

AN:

86254

European-Finnish (FIN)

AF:

0.128

AC:

6819

AN:

53418

Middle Eastern (MID)

AF:

0.165

AC:

951

AN:

5768

European-Non Finnish (NFE)

AF:

0.175

AC:

194230

AN:

1111996

Other (OTH)

AF:

0.188

AC:

11358

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

15022

30044

45066

60088

75110

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7080

14160

21240

28320

35400

<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:

0.216

AC:

32881

AN:

151936

Hom.:

3891

Cov.:

AF XY:

0.215

AC XY:

15941

AN XY:

74298

show subpopulations

African (AFR)

AF:

0.314

AC:

13001

AN:

41382

American (AMR)

AF:

0.226

AC:

3454

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.200

AC:

692

AN:

3462

East Asian (EAS)

AF:

0.269

AC:

1385

AN:

5152

South Asian (SAS)

AF:

0.138

AC:

665

AN:

4818

European-Finnish (FIN)

AF:

0.125

AC:

1326

AN:

10582

Middle Eastern (MID)

AF:

0.180

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.171

AC:

11621

AN:

67950

Other (OTH)

AF:

0.211

AC:

445

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1262

2524

3786

5048

6310

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

328

656

984

1312

1640

<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:

0.190

Hom.:

9833

Bravo

AF:

0.227

TwinsUK

AF:

0.172

AC:

638

ALSPAC

AF:

0.181

AC:

698

ESP6500AA

AF:

0.308

AC:

1359

ESP6500EA

AF:

0.174

AC:

1493

ExAC

AF:

0.188

AC:

22821

Asia WGS

AF:

0.242

AC:

845

AN:

3478

EpiCase

AF:

0.175

EpiControl

AF:

0.173

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.82

BayesDel_noAF

Benign

-0.81

CADD

Benign

7.0

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0072

.;T

Eigen

Benign

-0.95

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.038

LIST_S2

Benign

0.41

T;T

MetaRNN

Benign

0.0054

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.94

.;L

PhyloP100

-0.36

PrimateAI

Benign

0.23

PROVEAN

Benign

-1.9

N;N

REVEL

Benign

0.11

Sift

Benign

0.15

T;T

Sift4G

Benign

0.13

T;T

Polyphen

0.99

D;P

Vest4

0.14

MPC

0.065

ClinPred

0.014

GERP RS

-2.4

Varity_R

0.052

gMVP

0.061

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