10-128103561-T-C

Position:

• chr10-128103561-T-C

Variant summary

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

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. 13/20 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 0.22 (3891 hom., cov: 32)
  • Exomes 𝑓: 0.18 (24346 hom.)
• Consequence: MKI67 NM_002417.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.363

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=0.0054243207).
• 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/exons	MANE	Protein	UniProt
MKI67	NM_002417.5	c.8279A>G	p.Asp2760Gly	missense_variant	13/15	ENST00000368654.8	NP_002408.3
MKI67	NM_001145966.2	c.7199A>G	p.Asp2400Gly	missense_variant	12/14		NP_001139438.1
MKI67	XM_011539818.3	c.7247A>G	p.Asp2416Gly	missense_variant	10/12		XP_011538120.1
MKI67	XM_006717864.4	c.5957A>G	p.Asp1986Gly	missense_variant	2/4		XP_006717927.2

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.216 AC: 32865 AN: 151818 Hom.: 3892 Cov.: 32

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

GnomAD3 exomes AF: 0.190 AC: 47680 AN: 251194 Hom.: 4829 AF XY: 0.183 AC XY: 24784 AN XY: 135750

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 SAS exome AF: 0.140

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.: 78 AF XY: 0.177 AC XY: 129011 AN XY: 727236

Gnomad4 AFR exome AF: 0.313

Gnomad4 AMR exome AF: 0.224

Gnomad4 ASJ exome AF: 0.204

Gnomad4 EAS exome AF: 0.275

Gnomad4 SAS exome AF: 0.141

Gnomad4 FIN exome AF: 0.128

Gnomad4 NFE exome AF: 0.175

Gnomad4 OTH exome AF: 0.188

GnomAD4 genome AF: 0.216 AC: 32881 AN: 151936 Hom.: 3891 Cov.: 32 AF XY: 0.215 AC XY: 15941 AN XY: 74298

Gnomad4 AFR AF: 0.314

Gnomad4 AMR AF: 0.226

Gnomad4 ASJ AF: 0.200

Gnomad4 EAS AF: 0.269

Gnomad4 SAS AF: 0.138

Gnomad4 FIN AF: 0.125

Gnomad4 NFE AF: 0.171

Gnomad4 OTH AF: 0.211

Alfa AF: 0.184 Hom.: 6567

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	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.0
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0072	.;T
Eigen	Benign	-0.95
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.41	T;T
MetaRNN	Benign	0.0054	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.94	.;L
PrimateAI	Benign	0.23	T
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	T
GERP RS		-2.4
Varity_R		0.052
gMVP		0.061

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: rs10082391; hg19: chr10-129901825; COSMIC: COSV64073322; COSMIC: COSV64073322;