X-101127612-C-G

Variant names:

• chrX-101127612-C-G
• rs772648211
• NM_001386188.2:c.1021C>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001386188.2(CENPI):​c.1021C>G​(p.Leu341Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,192,984 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000025 (0 hom. 11 hem.)
• Consequence: CENPI NM_001386188.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.39
• Publications: 0 publications found

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]

CENPI Gene-Disease associations (from GenCC):

• idiopathic steroid-sensitive nephrotic syndrome

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06632644).
• BS2: High Hemizygotes in GnomAdExome4 at 11 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001386188.2. 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
	CENPI	NM_001386188.2	MANE Select	c.1021C>G	p.Leu341Val	missense	Exon 11 of 22	NP_001373117.1	Q92674-1
	CENPI	NM_006733.3		c.1021C>G	p.Leu341Val	missense	Exon 10 of 21	NP_006724.2	Q92674-1
	CENPI	NM_001318521.2		c.1021C>G	p.Leu341Val	missense	Exon 11 of 21	NP_001305450.1	A0A8C8KX99

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CENPI	ENST00000682095.1	MANE Select	c.1021C>G	p.Leu341Val	missense	Exon 11 of 22	ENSP00000507927.1	Q92674-1
	CENPI	ENST00000372927.5	TSL:5	c.1021C>G	p.Leu341Val	missense	Exon 10 of 21	ENSP00000362018.1	Q92674-1
	CENPI	ENST00000684367.1		c.1021C>G	p.Leu341Val	missense	Exon 12 of 23	ENSP00000507595.1	Q92674-1

Frequencies

GnomAD3 genomes AF: 0.00000887 AC: 1 AN: 112695 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000944

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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

GnomAD2 exomes AF: 0.0000238 AC: 4 AN: 168249 AF XY: 0.0000368

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000413

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000390

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000250 AC: 27 AN: 1080289 Hom.: 0 Cov.: 27 AF XY: 0.0000317 AC XY: 11 AN XY: 347541

African (AFR) AF: 0.00 AC: 0 AN: 25804

American (AMR) AF: 0.00 AC: 0 AN: 33314

Ashkenazi Jewish (ASJ) AF: 0.0000529 AC: 1 AN: 18890

East Asian (EAS) AF: 0.00 AC: 0 AN: 29743

South Asian (SAS) AF: 0.000138 AC: 7 AN: 50728

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40209

Middle Eastern (MID) AF: 0.000518 AC: 2 AN: 3861

European-Non Finnish (NFE) AF: 0.0000192 AC: 16 AN: 832381

Other (OTH) AF: 0.0000220 AC: 1 AN: 45359

GnomAD4 genome AF: 0.00000887 AC: 1 AN: 112695 Hom.: 0 Cov.: 23 AF XY: 0.0000287 AC XY: 1 AN XY: 34841

African (AFR) AF: 0.00 AC: 0 AN: 31073

American (AMR) AF: 0.0000944 AC: 1 AN: 10590

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2661

East Asian (EAS) AF: 0.00 AC: 0 AN: 3611

South Asian (SAS) AF: 0.00 AC: 0 AN: 2752

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6197

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53368

Other (OTH) AF: 0.00 AC: 0 AN: 1518

Alfa AF: 0.000187 Hom.: 1

Bravo AF: 0.0000453

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.11
DANN	Benign	0.57
DEOGEN2	Benign	0.059	T
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		-1.4
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.080
Sift	Benign	0.48	T
Sift4G	Benign	1.0	T
Polyphen		0.039	B
Vest4		0.19
MutPred		0.69		Loss of disorder (P = 0.1184)
MVP		0.20
MPC		0.39
ClinPred		0.034	T
GERP RS		-7.4
Varity_R		0.13
gMVP		0.39
Mutation Taster		=100/0	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: rs772648211; hg19: chrX-100382601;