NM_002417.5:c.9704A>G

Variant names:

• chr10-128101259-T-C
• rs35120165
• NM_002417.5:c.9704A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002417.5(MKI67):​c.9704A>G​(p.Lys3235Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00204 in 1,607,284 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (32 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (29 hom.)
• Consequence: MKI67 NM_002417.5 missense, splice_region
• Scores: Splicing: ADA: 0.2164
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.557
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018297732).
• BP6: Variant 10-128101259-T-C is Benign according to our data. Variant chr10-128101259-T-C is described in ClinVar as Benign. ClinVar VariationId is 780919.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0109 (1666/152350) while in subpopulation AFR AF = 0.0381 (1585/41564). AF 95% confidence interval is 0.0366. There are 32 homozygotes in GnomAd4. There are 796 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 32 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002417.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MKI67	NM_002417.5	MANE Select	c.9704A>G	p.Lys3235Arg	missense splice_region	Exon 14 of 15	NP_002408.3
	MKI67	NM_001145966.2		c.8624A>G	p.Lys2875Arg	missense splice_region	Exon 13 of 14	NP_001139438.1	P46013-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MKI67	ENST00000368654.8	TSL:2 MANE Select	c.9704A>G	p.Lys3235Arg	missense splice_region	Exon 14 of 15	ENSP00000357643.3	P46013-1
	MKI67	ENST00000935442.1		c.9698A>G	p.Lys3233Arg	missense splice_region	Exon 14 of 15	ENSP00000605501.1
	MKI67	ENST00000368653.7	TSL:2	c.8624A>G	p.Lys2875Arg	missense splice_region	Exon 13 of 14	ENSP00000357642.3	P46013-2

Frequencies

GnomAD3 genomes AF: 0.0109 AC: 1661 AN: 152232 Hom.: 33 Cov.: 33

Gnomad AFR AF: 0.0381

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.00286 AC: 716 AN: 250158 AF XY: 0.00197

Gnomad AFR exome AF: 0.0403

Gnomad AMR exome AF: 0.000958

Gnomad ASJ exome AF: 0.00110

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.000821

GnomAD4 exome AF: 0.00111 AC: 1619 AN: 1454934 Hom.: 29 Cov.: 30 AF XY: 0.000944 AC XY: 682 AN XY: 722212

African (AFR) AF: 0.0394 AC: 1310 AN: 33284

American (AMR) AF: 0.00135 AC: 60 AN: 44522

Ashkenazi Jewish (ASJ) AF: 0.000883 AC: 23 AN: 26042

East Asian (EAS) AF: 0.00 AC: 0 AN: 39538

South Asian (SAS) AF: 0.0000349 AC: 3 AN: 85978

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53358

Middle Eastern (MID) AF: 0.00105 AC: 6 AN: 5724

European-Non Finnish (NFE) AF: 0.0000551 AC: 61 AN: 1106404

Other (OTH) AF: 0.00260 AC: 156 AN: 60084

GnomAD4 genome AF: 0.0109 AC: 1666 AN: 152350 Hom.: 32 Cov.: 33 AF XY: 0.0107 AC XY: 796 AN XY: 74506

African (AFR) AF: 0.0381 AC: 1585 AN: 41564

American (AMR) AF: 0.00359 AC: 55 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68040

Other (OTH) AF: 0.00804 AC: 17 AN: 2114

Alfa AF: 0.00500 Hom.: 19

Bravo AF: 0.0126

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0379 AC: 167

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00358 AC: 434

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.014	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.97	L
PhyloP100		0.56
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.034
Sift	Benign	0.049	D
Sift4G	Uncertain	0.059	T
Polyphen		0.24	B
Vest4		0.13
MVP		0.15
MPC		0.093
ClinPred		0.0070	T
GERP RS		0.72
Varity_R		0.026
gMVP		0.027
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.22
dbscSNV1_RF	Benign	0.44
SpliceAI score (max)		0.030		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: rs35120165; hg19: chr10-129899523; COSMIC: COSV104424701;