10-128103237-G-C

Variant names:

• chr10-128103237-G-C
• rs2071496
• NM_002417.5:c.8603C>G

Variant summary

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

The NM_002417.5(MKI67):​c.8603C>G​(p.Thr2868Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.238 in 1,614,008 control chromosomes in the GnomAD database, including 47,225 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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.20 (3709 hom., cov: 32)
  • Exomes 𝑓: 0.24 (43516 hom.)
• Consequence: MKI67 NM_002417.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.814

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=0.00476712).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.266 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MKI67	NM_002417.5	c.8603C>G	p.Thr2868Ser	missense_variant	Exon 13 of 15	ENST00000368654.8	NP_002408.3
MKI67	NM_001145966.2	c.7523C>G	p.Thr2508Ser	missense_variant	Exon 12 of 14		NP_001139438.1
MKI67	XM_011539818.3	c.7571C>G	p.Thr2524Ser	missense_variant	Exon 10 of 12		XP_011538120.1
MKI67	XM_006717864.4	c.6281C>G	p.Thr2094Ser	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	c.8603C>G	p.Thr2868Ser	missense_variant	Exon 13 of 15	2	NM_002417.5	ENSP00000357643.3
MKI67	ENST00000368653.7	c.7523C>G	p.Thr2508Ser	missense_variant	Exon 12 of 14	2		ENSP00000357642.3
MKI67	ENST00000464771.1	n.-109C>G		upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.205 AC: 31162 AN: 152010 Hom.: 3702 Cov.: 32

Gnomad AFR AF: 0.0939

Gnomad AMI AF: 0.330

Gnomad AMR AF: 0.272

Gnomad ASJ AF: 0.296

Gnomad EAS AF: 0.128

Gnomad SAS AF: 0.203

Gnomad FIN AF: 0.293

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.239

GnomAD3 exomes AF: 0.242 AC: 60883 AN: 251420 Hom.: 7998 AF XY: 0.241 AC XY: 32807 AN XY: 135884

Gnomad AFR exome AF: 0.0886

Gnomad AMR exome AF: 0.325

Gnomad ASJ exome AF: 0.305

Gnomad EAS exome AF: 0.117

Gnomad SAS exome AF: 0.211

Gnomad FIN exome AF: 0.287

Gnomad NFE exome AF: 0.252

Gnomad OTH exome AF: 0.265

GnomAD4 exome AF: 0.241 AC: 352262 AN: 1461880 Hom.: 43516 Cov.: 81 AF XY: 0.241 AC XY: 174984 AN XY: 727244

Gnomad4 AFR exome AF: 0.0865

Gnomad4 AMR exome AF: 0.319

Gnomad4 ASJ exome AF: 0.298

Gnomad4 EAS exome AF: 0.160

Gnomad4 SAS exome AF: 0.210

Gnomad4 FIN exome AF: 0.291

Gnomad4 NFE exome AF: 0.244

Gnomad4 OTH exome AF: 0.233

GnomAD4 genome AF: 0.205 AC: 31170 AN: 152128 Hom.: 3709 Cov.: 32 AF XY: 0.208 AC XY: 15434 AN XY: 74364

Gnomad4 AFR AF: 0.0936

Gnomad4 AMR AF: 0.273

Gnomad4 ASJ AF: 0.296

Gnomad4 EAS AF: 0.128

Gnomad4 SAS AF: 0.203

Gnomad4 FIN AF: 0.293

Gnomad4 NFE AF: 0.242

Gnomad4 OTH AF: 0.238

Alfa AF: 0.240 Hom.: 1502

Bravo AF: 0.203

TwinsUK AF: 0.239 AC: 888

ALSPAC AF: 0.244 AC: 942

ESP6500AA AF: 0.0942 AC: 415

ESP6500EA AF: 0.248 AC: 2130

ExAC AF: 0.236 AC: 28632

Asia WGS AF: 0.152 AC: 528 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	0.16
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.2
DANN	Benign	0.74
DEOGEN2	Benign	0.0080	.;T
Eigen	Benign	-0.87
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.33	T;T
MetaRNN	Benign	0.0048	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	.;L
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.93	N;N
REVEL	Benign	0.028
Sift	Benign	0.19	T;T
Sift4G	Benign	0.40	T;T
Polyphen		0.98	D;P
Vest4		0.075
MutPred		0.31		.;Loss of loop (P = 0.0288);
MPC		0.15
ClinPred		0.010	T
GERP RS		-2.3
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.054
gMVP		0.035

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: rs2071496; hg19: chr10-129901501; COSMIC: COSV64072613; COSMIC: COSV64072613;