1-243126654-G-A

Variant names:

• chr1-243126654-G-A
• rs561098524
• NM_014812.3:c.4550C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_014812.3(CEP170):​c.4550C>T​(p.Pro1517Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000103 in 1,559,412 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: CEP170 NM_014812.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.95
• Publications: 0 publications found

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]

ENSG00000227230 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1165337).
• BS2: High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP170	NM_014812.3	c.4550C>T	p.Pro1517Leu	missense_variant	Exon 20 of 20	ENST00000366542.6	NP_055627.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP170	ENST00000366542.6	c.4550C>T	p.Pro1517Leu	missense_variant	Exon 20 of 20	5	NM_014812.3	ENSP00000355500.1
CEP170	ENST00000366544.6	c.4256C>T	p.Pro1419Leu	missense_variant	Exon 19 of 19	5		ENSP00000355502.1
CEP170	ENST00000366543.5	c.4178C>T	p.Pro1393Leu	missense_variant	Exon 19 of 19	5		ENSP00000355501.1

Frequencies

GnomAD3 genomes AF: 0.0000658 AC: 10 AN: 152076 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000874 AC: 14 AN: 160166 AF XY: 0.0000945

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000223

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000107 AC: 151 AN: 1407218 Hom.: 0 Cov.: 31 AF XY: 0.0000994 AC XY: 69 AN XY: 694398

African (AFR) AF: 0.00 AC: 0 AN: 32124

American (AMR) AF: 0.0000274 AC: 1 AN: 36546

Ashkenazi Jewish (ASJ) AF: 0.0000397 AC: 1 AN: 25216

East Asian (EAS) AF: 0.00 AC: 0 AN: 36832

South Asian (SAS) AF: 0.0000125 AC: 1 AN: 80120

European-Finnish (FIN) AF: 0.0000199 AC: 1 AN: 50372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5688

European-Non Finnish (NFE) AF: 0.000134 AC: 145 AN: 1081872

Other (OTH) AF: 0.0000342 AC: 2 AN: 58448

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152194 Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1 AN XY: 74414

African (AFR) AF: 0.0000241 AC: 1 AN: 41514

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000718

ExAC AF: 0.0000711 AC: 8

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4550C>T (p.P1517L) alteration is located in exon 20 (coding exon 19) of the CEP170 gene. This alteration results from a C to T substitution at nucleotide position 4550, causing the proline (P) at amino acid position 1517 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	Benign	0.087
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T;.;.;.;T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.93	.;.;.;D;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.12	T;T;T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.97	L;.;.;.;.
PhyloP100		5.9
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-2.2	N;N;N;D;D
REVEL	Benign	0.11
Sift	Uncertain	0.012	D;D;D;D;D
Sift4G	Uncertain	0.039	D;T;D;T;T
Polyphen		0.94	P;P;P;.;.
Vest4		0.21
MVP		0.67
ClinPred		0.29	T
GERP RS		4.8
Varity_R		0.064
gMVP		0.47
Mutation Taster		=84/16	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: rs561098524; hg19: chr1-243289956;