rs61893682

chr11-62150080-G-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP5 BP4 BS2

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. 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

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

Verdict is Likely_benign. Variant got -4 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 id 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 GnomAd at 381 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INCENP	NM_001040694.2	c.2415G>C	p.Gln805His	missense_variant	18/19	ENST00000394818.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INCENP	ENST00000394818.8	c.2415G>C	p.Gln805His	missense_variant	18/19	1	NM_001040694.2	P2
INCENP	ENST00000278849.4	c.2403G>C	p.Gln801His	missense_variant	17/18	5		A2

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

GnomAD3 exomes AF: 0.00278 AC: 699 AN: 251344 Hom.: 1 AF XY: 0.00286 AC XY: 389 AN XY: 135880

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 SAS exome AF: 0.00144

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

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00174

Gnomad4 FIN exome AF: 0.0114

Gnomad4 NFE exome AF: 0.00320

Gnomad4 OTH exome AF: 0.00179

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

Gnomad4 AFR AF: 0.000650

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.0119

Gnomad4 NFE AF: 0.00316

Gnomad4 OTH AF: 0.000473

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

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Nephronophthisis Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Yale Center for Mendelian Genomics, Yale University

Dec 23, 2015

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Computational scores

Source: dbNSFP v4.3

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;T
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	M;.
MutationTaster	Benign	0.96	D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.2	N;N
REVEL	Benign	0.13
Sift	Uncertain	0.012	D;D
Sift4G	Benign	0.091	T;T
Polyphen		0.99	D;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs61893682; hg19: chr11-61917552; COSMIC: COSV99074628; COSMIC: COSV99074628;