chr9-92379847-T-G

Variant names:

• chr9-92379847-T-G
• NM_001012267.3:c.552T>G

Variant summary

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

The NM_001012267.3(CENPP):​c.552T>G​(p.Phe184Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000894 in 1,454,796 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: CENPP NM_001012267.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.74

Genes affected

CENPP (HGNC:32933): (centromere protein P) CENPP is a subunit of a CENPH (MIM 605607)-CENPI (MIM 300065)-associated centromeric complex that targets CENPA (MIM 117139) to centromeres and is required for proper kinetochore function and mitotic progression (Okada et al., 2006 [PubMed 16622420]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CENPP	NM_001012267.3	c.552T>G	p.Phe184Leu	missense_variant	Exon 5 of 8	ENST00000375587.8	NP_001012267.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CENPP	ENST00000375587.8	c.552T>G	p.Phe184Leu	missense_variant	Exon 5 of 8	1	NM_001012267.3	ENSP00000364737.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000894 AC: 13 AN: 1454796 Hom.: 0 Cov.: 27 AF XY: 0.00000690 AC XY: 5 AN XY: 724262

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: 0.0000118

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 01, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.552T>G (p.F184L) alteration is located in exon 5 (coding exon 5) of the CENPP gene. This alteration results from a T to G substitution at nucleotide position 552, causing the phenylalanine (F) at amino acid position 184 to be replaced by a leucine (L). 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	Pathogenic	0.88
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;T
Eigen	Benign	0.091
Eigen_PC	Benign	0.086
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.48	T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.4	M;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-4.1	D;.
REVEL	Uncertain	0.46
Sift	Uncertain	0.013	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.88	P;.
Vest4		0.81
MutPred		0.66		Loss of methylation at K181 (P = 0.1032);Loss of methylation at K181 (P = 0.1032);
MVP		0.27
MPC		0.34
ClinPred		0.98	D
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.44
gMVP		0.59

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: chr9-95142129;