chr10-128113592-C-G

Variant names:

• chr10-128113592-C-G
• rs11016076
• NM_002417.5:c.1491G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

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. 13/21 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 (4033 hom., cov: 33)
  • Exomes 𝑓: 0.18 (24994 hom.)
• Consequence: MKI67 NM_002417.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.257
• Publications: 23 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
MKI67	NM_002417.5	c.1491G>C	p.Glu497Asp	missense_variant	Exon 8 of 15	ENST00000368654.8	NP_002408.3
MKI67	NM_001145966.2	c.411G>C	p.Glu137Asp	missense_variant	Exon 7 of 14		NP_001139438.1
MKI67	XM_011539818.3	c.459G>C	p.Glu153Asp	missense_variant	Exon 5 of 12		XP_011538120.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MKI67	ENST00000368654.8	c.1491G>C	p.Glu497Asp	missense_variant	Exon 8 of 15	2	NM_002417.5	ENSP00000357643.3
MKI67	ENST00000368653.7	c.411G>C	p.Glu137Asp	missense_variant	Exon 7 of 14	2		ENSP00000357642.3

Frequencies

GnomAD3 genomes AF: 0.220 AC: 33443 AN: 152046 Hom.: 4034 Cov.: 33

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

GnomAD2 exomes AF: 0.192 AC: 48207 AN: 251266 AF XY: 0.184

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 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.: 32 AF XY: 0.180 AC XY: 130626 AN XY: 726778

African (AFR) AF: 0.320 AC: 10716 AN: 33442

American (AMR) AF: 0.226 AC: 10091 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.204 AC: 5338 AN: 26126

East Asian (EAS) AF: 0.274 AC: 10890 AN: 39674

South Asian (SAS) AF: 0.141 AC: 12132 AN: 86230

European-Finnish (FIN) AF: 0.125 AC: 6667 AN: 53412

Middle Eastern (MID) AF: 0.165 AC: 954 AN: 5766

European-Non Finnish (NFE) AF: 0.177 AC: 197145 AN: 1111128

Other (OTH) AF: 0.190 AC: 11445 AN: 60358

GnomAD4 genome AF: 0.220 AC: 33458 AN: 152164 Hom.: 4033 Cov.: 33 AF XY: 0.217 AC XY: 16171 AN XY: 74402

African (AFR) AF: 0.322 AC: 13353 AN: 41482

American (AMR) AF: 0.226 AC: 3461 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.200 AC: 694 AN: 3472

East Asian (EAS) AF: 0.268 AC: 1390 AN: 5182

South Asian (SAS) AF: 0.138 AC: 665 AN: 4830

European-Finnish (FIN) AF: 0.123 AC: 1299 AN: 10604

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.174 AC: 11853 AN: 67996

Other (OTH) AF: 0.213 AC: 449 AN: 2110

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	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	13
DANN	Uncertain	1.0
DEOGEN2	Benign	0.030	.;T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.44	T;T
MetaRNN	Benign	0.0032	T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.1	.;M
PhyloP100		0.26
PrimateAI	Benign	0.38	T
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	T
GERP RS		0.71
Varity_R		0.070
gMVP		0.13
Mutation Taster		=98/2	polymorphism (auto)

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: rs11016076; hg19: chr10-129911856; COSMIC: COSV64073339; COSMIC: COSV64073339;