X-101148109-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001386188.2(CENPI):c.2042A>G(p.Asn681Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000589 in 1,187,692 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 28 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000063 (0 hom. 27 hem.)
• Consequence: CENPI NM_001386188.2 missense
• Clinical Significance: Likely benign no assertion criteria provided B:2
• Conservation: PhyloP100: 3.58

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03136486).
• BP6: Variant X-101148109-A-G is Benign according to our data. Variant chrX-101148109-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1205920.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-101148109-A-G is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAdExome at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CENPI	NM_001386188.2	c.2042A>G	p.Asn681Ser	missense_variant	20/22	ENST00000682095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CENPI	ENST00000682095.1	c.2042A>G	p.Asn681Ser	missense_variant	20/22		NM_001386188.2	P2
CENPI	ENST00000372927.5	c.2042A>G	p.Asn681Ser	missense_variant	19/21	5		P2
CENPI	ENST00000684367.1	c.2042A>G	p.Asn681Ser	missense_variant	21/23			P2
CENPI	ENST00000423383.3	c.2042A>G	p.Asn681Ser	missense_variant	20/21	5		A2

Frequencies

GnomAD3 genomes AF: 0.0000179 AC: 2 AN: 112040 Hom.: 0 Cov.: 23 AF XY: 0.0000292 AC XY: 1 AN XY: 34190

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000557

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000832 AC: 13 AN: 156224 Hom.: 0 AF XY: 0.0000799 AC XY: 4 AN XY: 50058

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000886

Gnomad SAS exome AF: 0.0000773

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000270

GnomAD4 exome AF: 0.0000632 AC: 68 AN: 1075599 Hom.: 0 Cov.: 29 AF XY: 0.0000770 AC XY: 27 AN XY: 350691

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00156

Gnomad4 SAS exome AF: 0.000282

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000599

Gnomad4 OTH exome AF: 0.0000222

GnomAD4 genome AF: 0.0000178 AC: 2 AN: 112093 Hom.: 0 Cov.: 23 AF XY: 0.0000292 AC XY: 1 AN XY: 34253

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000559

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ExAC AF: 0.0000989 AC: 12

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: no assertion criteria provided

Submissions by phenotype

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	14
Dann	Benign	0.72
DEOGEN2	Benign	0.070	T;T
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.031	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.99	N;N
REVEL	Benign	0.17
Sift	Benign	0.12	T;T
Sift4G	Benign	0.16	T;T
Polyphen		0.13	B;B
Vest4		0.47
MVP		0.51
MPC		0.31
ClinPred		0.027	T
GERP RS		3.2
Varity_R		0.089
gMVP		0.46

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

LitVar

Other links and lift over

dbSNP: rs181641011; hg19: chrX-100403098;