chr11-62129814-T-A

Variant names:

• chr11-62129814-T-A
• rs373398703
• NM_001040694.2:c.287T>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001040694.2(INCENP):​c.287T>A​(p.Leu96Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. L96P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: INCENP NM_001040694.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.696
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0765796).

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.287T>A	p.Leu96Gln	missense	Exon 4 of 19	NP_001035784.1	Q9NQS7-1
	INCENP	NM_020238.3		c.287T>A	p.Leu96Gln	missense	Exon 4 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.287T>A	p.Leu96Gln	missense	Exon 4 of 19	ENSP00000378295.3	Q9NQS7-1
	INCENP	ENST00000528037.1	TSL:1	n.451T>A		non_coding_transcript_exon	Exon 4 of 5
	INCENP	ENST00000887855.1		c.287T>A	p.Leu96Gln	missense	Exon 4 of 18	ENSP00000557914.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	7.4
DANN	Benign	0.90
DEOGEN2	Benign	0.031	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.077	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		-0.70
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.059
Sift	Benign	0.16	T
Sift4G	Benign	0.31	T
Polyphen		0.38	B
Vest4		0.20
MutPred		0.15		Gain of solvent accessibility (P = 0.0837)
MVP		0.22
MPC		0.28
ClinPred		0.27	T
GERP RS		-3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.072
gMVP		0.13
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs373398703; hg19: chr11-61897286;