X-101148082-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001386188.2(CENPI):c.2015G>C(p.Gly672Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000187 in 1,067,148 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 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)
  • Exomes 𝑓: 0.0000019 (0 hom. 0 hem.)
• Consequence: CENPI NM_001386188.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.767

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17062587).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CENPI	NM_001386188.2	c.2015G>C	p.Gly672Ala	missense_variant	20/22	ENST00000682095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CENPI	ENST00000682095.1	c.2015G>C	p.Gly672Ala	missense_variant	20/22		NM_001386188.2	P2
CENPI	ENST00000372927.5	c.2015G>C	p.Gly672Ala	missense_variant	19/21	5		P2
CENPI	ENST00000684367.1	c.2015G>C	p.Gly672Ala	missense_variant	21/23			P2
CENPI	ENST00000423383.3	c.2015G>C	p.Gly672Ala	missense_variant	20/21	5		A2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000187 AC: 2 AN: 1067148 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 346302

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000241

Gnomad4 OTH exome AF: 0.00

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

Aug 08, 2022

The c.2015G>C (p.G672A) alteration is located in exon 19 (coding exon 18) of the CENPI gene. This alteration results from a G to C substitution at nucleotide position 2015, causing the glycine (G) at amino acid position 672 to be replaced by an alanine (A). 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	0.082
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	7.7
Dann	Benign	0.69
DEOGEN2	Benign	0.050	T;T
FATHMM_MKL	Benign	0.55	D
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.57	N;N
REVEL	Benign	0.043
Sift	Benign	0.18	T;T
Sift4G	Benign	0.53	T;T
Polyphen		0.0020	B;B
Vest4		0.073
MutPred		0.70		Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);
MVP		0.42
MPC		0.41
ClinPred		0.066	T
GERP RS		1.3
Varity_R		0.070
gMVP		0.37

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-100403071;