chr1-173807452-G-C

Variant names:

• chr1-173807452-G-C
• rs780132844
• NM_001387287.1:c.235C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001387287.1(CENPL):​c.235C>G​(p.Pro79Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P79S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CENPL NM_001387287.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.42
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.932

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CENPL	NM_001387287.1	c.235C>G	p.Pro79Ala	missense_variant	Exon 4 of 6	ENST00000682279.1	NP_001374216.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CENPL	ENST00000682279.1	c.235C>G	p.Pro79Ala	missense_variant	Exon 4 of 6		NM_001387287.1	ENSP00000507473.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1447906 Hom.: 0 Cov.: 29 AF XY: 0.00000139 AC XY: 1 AN XY: 720754

African (AFR) AF: 0.00 AC: 0 AN: 33230

American (AMR) AF: 0.00 AC: 0 AN: 44518

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25762

East Asian (EAS) AF: 0.00 AC: 0 AN: 39564

South Asian (SAS) AF: 0.00 AC: 0 AN: 84690

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52836

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 9.07e-7 AC: 1 AN: 1101944

Other (OTH) AF: 0.00 AC: 0 AN: 59644

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	.;T;T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;.;D
M_CAP	Uncertain	0.098	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Uncertain	0.051	D
MutationAssessor	Uncertain	2.6	M;M;M
PhyloP100		8.4
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-4.8	D;D;D
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.81
MutPred		0.80		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.68
MPC		0.54
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.70
gMVP		0.71
Mutation Taster		=24/76	disease causing

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: rs780132844; hg19: chr1-173776590;