1-243156309-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 8P and 10B. PVS1 BP6_Moderate BS1 BS2

The ENST00000490813.5(CEP170):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0314 in 1,592,400 control chromosomes in the GnomAD database, including 879 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.023 (45 hom., cov: 30)
  • Exomes 𝑓: 0.032 (834 hom.)
• Consequence: CEP170 ENST00000490813.5 start_lost
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.33

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• BP6: Variant 1-243156309-T-C is Benign according to our data. Variant chr1-243156309-T-C is described in ClinVar as [Benign]. Clinvar id is 773423.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0228 (3435/150854) while in subpopulation NFE AF= 0.0346 (2347/67796). AF 95% confidence interval is 0.0335. There are 45 homozygotes in gnomad4. There are 1591 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd at 3436 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP170	NM_014812.3	c.3823A>G	p.Met1275Val	missense_variant	14/20	ENST00000366542.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP170	ENST00000366542.6	c.3823A>G	p.Met1275Val	missense_variant	14/20	5	NM_014812.3	P1

Frequencies

GnomAD3 genomes AF: 0.0228 AC: 3436 AN: 150736 Hom.: 45 Cov.: 30

Gnomad AFR AF: 0.00696

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0216

Gnomad ASJ AF: 0.0246

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.0111

Gnomad FIN AF: 0.0263

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0346

Gnomad OTH AF: 0.0311

GnomAD3 exomes AF: 0.0240 AC: 4965 AN: 206808 Hom.: 98 AF XY: 0.0239 AC XY: 2642 AN XY: 110738

Gnomad AFR exome AF: 0.00657

Gnomad AMR exome AF: 0.0174

Gnomad ASJ exome AF: 0.0228

Gnomad EAS exome AF: 0.0000662

Gnomad SAS exome AF: 0.0107

Gnomad FIN exome AF: 0.0303

Gnomad NFE exome AF: 0.0349

Gnomad OTH exome AF: 0.0290

GnomAD4 exome AF: 0.0323 AC: 46625 AN: 1441546 Hom.: 834 Cov.: 31 AF XY: 0.0315 AC XY: 22501 AN XY: 714940

Gnomad4 AFR exome AF: 0.00525

Gnomad4 AMR exome AF: 0.0184

Gnomad4 ASJ exome AF: 0.0226

Gnomad4 EAS exome AF: 0.0000512

Gnomad4 SAS exome AF: 0.0115

Gnomad4 FIN exome AF: 0.0319

Gnomad4 NFE exome AF: 0.0369

Gnomad4 OTH exome AF: 0.0299

GnomAD4 genome AF: 0.0228 AC: 3435 AN: 150854 Hom.: 45 Cov.: 30 AF XY: 0.0216 AC XY: 1591 AN XY: 73588

Gnomad4 AFR AF: 0.00694

Gnomad4 AMR AF: 0.0216

Gnomad4 ASJ AF: 0.0246

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0111

Gnomad4 FIN AF: 0.0263

Gnomad4 NFE AF: 0.0346

Gnomad4 OTH AF: 0.0308

Alfa AF: 0.0311 Hom.: 31

Bravo AF: 0.0222

TwinsUK AF: 0.0356 AC: 132

ALSPAC AF: 0.0405 AC: 156

ESP6500AA AF: 0.00653 AC: 24

ESP6500EA AF: 0.0366 AC: 298

ExAC AF: 0.0221 AC: 2659

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	17
Dann	Uncertain	0.98
DEOGEN2	Benign	0.012	T;.;.;.;T;.;T;T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.74	D
MetaRNN	Benign	0.0029	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;N;N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.47	N;N;N;N;N;N;N;N
REVEL	Benign	0.044
Sift	Benign	0.40	T;T;T;D;D;T;D;D
Sift4G	Benign	0.32	T;T;T;D;D;T;.;.
Polyphen		0.012	B;B;B;.;.;.;.;.
Vest4		0.31
ClinPred		0.0063	T
GERP RS		4.9
Varity_R		0.037
gMVP		0.081

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: rs148125417; hg19: chr1-243319611;