rs61893682

Variant names:

• chr11-62150080-G-C
• rs61893682
• NM_001040694.2:c.2415G>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP5 BP4 BS2_Supporting

The NM_001040694.2(INCENP):​c.2415G>C​(p.Gln805His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.003 in 1,613,998 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency:
  • Genomes: 𝑓 0.0025 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (8 hom.)
• Consequence: INCENP NM_001040694.2 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.916
• Publications: 4 publications found

Genes affected

INCENP (HGNC:6058): (inner centromere protein) In mammalian cells, 2 broad groups of centromere-interacting proteins have been described: constitutively binding centromere proteins and 'passenger,' or transiently interacting, proteins (reviewed by Choo, 1997). The constitutive proteins include CENPA (centromere protein A; MIM 117139), CENPB (MIM 117140), CENPC1 (MIM 117141), and CENPD (MIM 117142). The term 'passenger proteins' encompasses a broad collection of proteins that localize to the centromere during specific stages of the cell cycle (Earnshaw and Mackay, 1994 [PubMed 8088460]). These include CENPE (MIM 117143); MCAK (MIM 604538); KID (MIM 603213); cytoplasmic dynein (e.g., MIM 600112); CliPs (e.g., MIM 179838); and CENPF/mitosin (MIM 600236). The inner centromere proteins (INCENPs) (Earnshaw and Cooke, 1991 [PubMed 1860899]), the initial members of the passenger protein group, display a broad localization along chromosomes in the early stages of mitosis but gradually become concentrated at centromeres as the cell cycle progresses into mid-metaphase. During telophase, the proteins are located within the midbody in the intercellular bridge, where they are discarded after cytokinesis (Cutts et al., 1999 [PubMed 10369859]).[supplied by OMIM, Mar 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PP5: Variant 11-62150080-G-C is Pathogenic according to our data. Variant chr11-62150080-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 548641.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.010879815). . Strength limited to SUPPORTING due to the PP5.
• BS2: High AC in GnomAd4 at 381 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040694.2. 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
	INCENP	NM_001040694.2	MANE Select	c.2415G>C	p.Gln805His	missense	Exon 18 of 19	NP_001035784.1	Q9NQS7-1
	INCENP	NM_020238.3		c.2403G>C	p.Gln801His	missense	Exon 17 of 18	NP_064623.2	Q9NQS7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INCENP	ENST00000394818.8	TSL:1 MANE Select	c.2415G>C	p.Gln805His	missense	Exon 18 of 19	ENSP00000378295.3	Q9NQS7-1
	INCENP	ENST00000887855.1		c.2436G>C	p.Gln812His	missense	Exon 17 of 18	ENSP00000557914.1
	INCENP	ENST00000887854.1		c.2415G>C	p.Gln805His	missense	Exon 17 of 18	ENSP00000557913.1

Frequencies

GnomAD3 genomes AF: 0.00250 AC: 381 AN: 152108 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0119

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00316

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00278 AC: 699 AN: 251344 AF XY: 0.00286

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0116

Gnomad NFE exome AF: 0.00321

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00305 AC: 4454 AN: 1461772 Hom.: 8 Cov.: 31 AF XY: 0.00300 AC XY: 2185 AN XY: 727192

African (AFR) AF: 0.000448 AC: 15 AN: 33480

American (AMR) AF: 0.000157 AC: 7 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00174 AC: 150 AN: 86256

European-Finnish (FIN) AF: 0.0114 AC: 608 AN: 53324

Middle Eastern (MID) AF: 0.00225 AC: 13 AN: 5768

European-Non Finnish (NFE) AF: 0.00320 AC: 3553 AN: 1111992

Other (OTH) AF: 0.00179 AC: 108 AN: 60394

GnomAD4 genome AF: 0.00250 AC: 381 AN: 152226 Hom.: 3 Cov.: 32 AF XY: 0.00289 AC XY: 215 AN XY: 74424

African (AFR) AF: 0.000650 AC: 27 AN: 41536

American (AMR) AF: 0.000327 AC: 5 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4820

European-Finnish (FIN) AF: 0.0119 AC: 126 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00316 AC: 215 AN: 68002

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00262 Hom.: 0

Bravo AF: 0.00164

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00372 AC: 32

ExAC AF: 0.00278 AC: 337

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00191

EpiControl AF: 0.00279

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Nephronophthisis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.85	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		-0.92
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.13
Sift	Uncertain	0.012	D
Sift4G	Benign	0.091	T
Polyphen		0.99	D
Vest4		0.37
MutPred		0.14		Gain of catalytic residue at Q805 (P = 0.076)
MVP		0.33
MPC		0.88
ClinPred		0.042	T
GERP RS		-3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.33
Mutation Taster		=99/1	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61893682; hg19: chr11-61917552; COSMIC: COSV99074628; COSMIC: COSV99074628;