1-173803193-A-G

Position:

• chr1-173803193-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001387287.1(CENPL):​c.733T>C​(p.Cys245Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CENPL NM_001387287.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.22

Genes affected

CENPL (HGNC:17879): (centromere protein L) CENPL 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]

CENPL (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05986625).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CENPL	NM_001387287.1	c.733T>C	p.Cys245Arg	missense_variant	5/6	ENST00000682279.1	NP_001374216.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CENPL	ENST00000682279.1	c.733T>C	p.Cys245Arg	missense_variant	5/6		NM_001387287.1	ENSP00000507473.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461256 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 726978

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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 20, 2024

The c.871T>C (p.C291R) alteration is located in exon 6 (coding exon 4) of the CENPL gene. This alteration results from a T to C substitution at nucleotide position 871, causing the cysteine (C) at amino acid position 291 to be replaced by an arginine (R). 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	0.15
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Benign	0.022	.;T;T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.60	T;.;T
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.060	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	.;L;L
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.023
Sift	Benign	0.37	T;T;T
Sift4G	Benign	0.27	T;T;T
Polyphen		0.061	B;B;B
Vest4		0.16
MutPred		0.31		.;Gain of disorder (P = 0.013);Gain of disorder (P = 0.013);
MVP		0.15
MPC		0.70
ClinPred		0.49	T
GERP RS		5.2
Varity_R		0.28
gMVP		0.70

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: rs956680000; hg19: chr1-173772331;