10-128108716-C-T

Position:

• chr10-128108716-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002417.5(MKI67):​c.3124G>A​(p.Gly1042Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.239 in 1,614,028 control chromosomes in the GnomAD database, including 47,492 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 0.21 (3894 hom., cov: 33)
  • Exomes 𝑓: 0.24 (43598 hom.)
• Consequence: MKI67 NM_002417.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.36

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0050908625).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.27 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MKI67	NM_002417.5	c.3124G>A	p.Gly1042Ser	missense_variant	13/15	ENST00000368654.8	NP_002408.3
MKI67	NM_001145966.2	c.2044G>A	p.Gly682Ser	missense_variant	12/14		NP_001139438.1
MKI67	XM_011539818.3	c.2092G>A	p.Gly698Ser	missense_variant	10/12		XP_011538120.1
MKI67	XM_006717864.4	c.802G>A	p.Gly268Ser	missense_variant	2/4		XP_006717927.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MKI67	ENST00000368654.8	c.3124G>A	p.Gly1042Ser	missense_variant	13/15	2	NM_002417.5	ENSP00000357643	P2
MKI67	ENST00000368653.7	c.2044G>A	p.Gly682Ser	missense_variant	12/14	2		ENSP00000357642	A2

Frequencies

GnomAD3 genomes AF: 0.215 AC: 32677 AN: 152038 Hom.: 3886 Cov.: 33

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.330

Gnomad AMR AF: 0.277

Gnomad ASJ AF: 0.297

Gnomad EAS AF: 0.128

Gnomad SAS AF: 0.203

Gnomad FIN AF: 0.294

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.246

GnomAD3 exomes AF: 0.245 AC: 61483 AN: 251406 Hom.: 8060 AF XY: 0.243 AC XY: 33017 AN XY: 135868

Gnomad AFR exome AF: 0.124

Gnomad AMR exome AF: 0.326

Gnomad ASJ exome AF: 0.305

Gnomad EAS exome AF: 0.116

Gnomad SAS exome AF: 0.211

Gnomad FIN exome AF: 0.288

Gnomad NFE exome AF: 0.252

Gnomad OTH exome AF: 0.267

GnomAD4 exome AF: 0.242 AC: 353424 AN: 1461872 Hom.: 43598 Cov.: 78 AF XY: 0.241 AC XY: 175463 AN XY: 727236

Gnomad4 AFR exome AF: 0.121

Gnomad4 AMR exome AF: 0.321

Gnomad4 ASJ exome AF: 0.298

Gnomad4 EAS exome AF: 0.159

Gnomad4 SAS exome AF: 0.210

Gnomad4 FIN exome AF: 0.291

Gnomad4 NFE exome AF: 0.244

Gnomad4 OTH exome AF: 0.235

GnomAD4 genome AF: 0.215 AC: 32696 AN: 152156 Hom.: 3894 Cov.: 33 AF XY: 0.217 AC XY: 16168 AN XY: 74392

Gnomad4 AFR AF: 0.128

Gnomad4 AMR AF: 0.277

Gnomad4 ASJ AF: 0.297

Gnomad4 EAS AF: 0.128

Gnomad4 SAS AF: 0.203

Gnomad4 FIN AF: 0.294

Gnomad4 NFE AF: 0.242

Gnomad4 OTH AF: 0.245

Alfa AF: 0.239 Hom.: 7794

Bravo AF: 0.215

TwinsUK AF: 0.238 AC: 883

ALSPAC AF: 0.244 AC: 941

ESP6500AA AF: 0.131 AC: 576

ESP6500EA AF: 0.247 AC: 2128

ExAC AF: 0.239 AC: 29014

Asia WGS AF: 0.153 AC: 532 AN: 3478

EpiCase AF: 0.251

EpiControl AF: 0.259

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.24
DANN	Benign	0.88
DEOGEN2	Benign	0.0091	.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0076	N
LIST_S2	Benign	0.38	T;T
MetaRNN	Benign	0.0051	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.42	.;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.30	N;N
REVEL	Benign	0.053
Sift	Benign	0.81	T;T
Sift4G	Benign	0.63	T;T
Polyphen		0.97	D;P
Vest4		0.030
MPC		0.25
ClinPred		0.0023	T
GERP RS		-4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.021
gMVP		0.074

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

Other links and lift over

dbSNP: rs2152143; hg19: chr10-129906980; COSMIC: COSV64072293; COSMIC: COSV64072293;