1-243126650-T-A

Position:

• chr1-243126650-T-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_014812.3(CEP170):​c.4554A>T​(p.Lys1518Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000135 in 1,408,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 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: 31)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: CEP170 NM_014812.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.404

Genes affected

CEP170 (HGNC:28920): (centrosomal protein 170) The product of this gene is a component of the centrosome, a non-membraneous organelle that functions as the major microtubule-organizing center in animal cells. During interphase, the encoded protein localizes to the sub-distal appendages of mature centrioles, which are microtubule-based structures thought to help organize centrosomes. During mitosis, the protein associates with spindle microtubules near the centrosomes. The protein interacts with and is phosphorylated by polo-like kinase 1, and functions in maintaining microtubule organization and cell morphology. The human genome contains a putative transcribed pseudogene. Several alternatively spliced transcript variants of this gene have been found, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Jul 2008]

CEP170 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17262644).
• BS2: High AC in GnomAdExome4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEP170	NM_014812.3	c.4554A>T	p.Lys1518Asn	missense_variant	20/20	ENST00000366542.6	NP_055627.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEP170	ENST00000366542.6	c.4554A>T	p.Lys1518Asn	missense_variant	20/20	5	NM_014812.3	ENSP00000355500.1
CEP170	ENST00000366544.5	c.4260A>T	p.Lys1420Asn	missense_variant	19/19	5		ENSP00000355502.1
CEP170	ENST00000366543.5	c.4182A>T	p.Lys1394Asn	missense_variant	19/19	5		ENSP00000355501.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000135 AC: 19 AN: 1408940 Hom.: 0 Cov.: 31 AF XY: 0.0000129 AC XY: 9 AN XY: 695430

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: 0.0000175

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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

Nov 14, 2024

The c.4554A>T (p.K1518N) alteration is located in exon 20 (coding exon 19) of the CEP170 gene. This alteration results from a A to T substitution at nucleotide position 4554, causing the lysine (K) at amino acid position 1518 to be replaced by an asparagine (N). 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	0.56
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.028	T;.;.;.;T
Eigen	Benign	-0.045
Eigen_PC	Benign	0.014
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.96	.;.;.;D;D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.17	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.97	L;.;.;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.1	N;N;N;N;N
REVEL	Benign	0.11
Sift	Uncertain	0.0060	D;D;D;D;D
Sift4G	Benign	0.30	T;T;T;D;D
Polyphen		1.0	D;D;D;.;.
Vest4		0.23
MutPred		0.18		Loss of methylation at K1518 (P = 0.0028);.;.;.;.;
MVP		0.59
ClinPred		0.63	D
GERP RS		3.7
Varity_R		0.11
gMVP		0.31

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: rs2053729876; hg19: chr1-243289952;