X-101127618-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001386188.2(CENPI):c.1027C>A(p.Gln343Lys) 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. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: CENPI NM_001386188.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.480

Genes affected

CENPI (HGNC:3968): (centromere protein I) This gene encodes a centromere protein that is a component of the CENPA-NAC (nucleosome-associated) complex. This complex is critical for accurate chromosome alignment and segregation and it ensures proper mitotic progression. This protein regulates the recruitment of kinetochore-associated proteins that are required to generate the spindle checkpoint signal. The product of this gene is involved in the response of gonadal tissues to follicle-stimulating hormone. Mutations in this gene may be involved in human X-linked disorders of gonadal development and gametogenesis. Alternate splicing results in multiple transcript variants. A pseudogene of this gene is found on chromosome 13. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36054784).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CENPI	NM_001386188.2	c.1027C>A	p.Gln343Lys	missense_variant	11/22	ENST00000682095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CENPI	ENST00000682095.1	c.1027C>A	p.Gln343Lys	missense_variant	11/22		NM_001386188.2	P2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2024

The c.1027C>A (p.Q343K) alteration is located in exon 10 (coding exon 9) of the CENPI gene. This alteration results from a C to A substitution at nucleotide position 1027, causing the glutamine (Q) at amino acid position 343 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	16
Dann	Uncertain	0.97
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.78	T;.;T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.36	T;T;T
MetaSVM	Benign	-0.29	T
MutationAssessor	Uncertain	2.6	M;M;M
MutationTaster	Benign	0.72	D;D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Benign	0.18
Sift	Benign	0.059	T;T;T
Sift4G	Benign	0.23	T;T;T
Polyphen		0.95	.;P;P
Vest4		0.24
MutPred		0.62		Gain of ubiquitination at Q343 (P = 0.0085);Gain of ubiquitination at Q343 (P = 0.0085);Gain of ubiquitination at Q343 (P = 0.0085);
MVP		0.54
MPC		0.49
ClinPred		0.40	T
GERP RS		3.5
Varity_R		0.29
gMVP		0.50

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-100382607;