10-93503308-G-A

Position:

chr10-93503308-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_018131.5(CEP55):c.379G>A(p.Val127Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000629 in 1,614,122 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. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V127L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00065 ( 0 hom. )

Consequence

CEP55
NM_018131.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: -0.189

Variant links:

Genes affected

CEP55 (HGNC:1161): (centrosomal protein 55) Enables identical protein binding activity. Involved in cranial skeletal system development; establishment of protein localization; and midbody abscission. Acts upstream of or within mitotic cytokinesis. Located in Flemming body; centriolar satellite; and plasma membrane. Implicated in multinucleated neurons, anhydramnios, renal dysplasia, cerebellar hypoplasia and hydranencephaly. [provided by Alliance of Genome Resources, Apr 2022]

CEP55 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.009529173).

BS1

Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000646 (944/1461840) while in subpopulation AMR AF= 0.000917 (41/44722). AF 95% confidence interval is 0.000699. There are 0 homozygotes in gnomad4_exome. There are 461 alleles in male gnomad4_exome subpopulation. Median coverage is 35. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP55	NM_018131.5 linkuse as main transcript	c.379G>A	p.Val127Ile	missense_variant	3/9	ENST00000371485.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP55	ENST00000371485.8 linkuse as main transcript	c.379G>A	p.Val127Ile	missense_variant	3/9	1	NM_018131.5	P1	Q53EZ4-1

Frequencies

GnomAD3 genomes

AF:

0.000473

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000706

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000569

AC:

143

AN:

251432

Hom.:

AF XY:

0.000655

AC XY:

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000867

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.000844

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000646

AC:

944

AN:

1461840

Hom.:

Cov.:

AF XY:

0.000634

AC XY:

461

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.000917

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000277

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.000131

Gnomad4 NFE exome

AF:

0.000742

Gnomad4 OTH exome

AF:

0.000679

GnomAD4 genome

AF:

0.000473

AC:

AN:

152282

Hom.:

Cov.:

AF XY:

0.000389

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000706

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000733

Hom.:

Bravo

AF:

0.000612

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000535

AC:

EpiCase

AF:

0.00104

EpiControl

AF:

0.00136

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 05, 2022

The c.379G>A (p.V127I) alteration is located in exon 3 (coding exon 2) of the CEP55 gene. This alteration results from a G to A substitution at nucleotide position 379, causing the valine (V) at amino acid position 127 to be replaced by an isoleucine (I). The p.V127I alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 12, 2022

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 127 of the CEP55 protein (p.Val127Ile). This variant is present in population databases (rs199894468, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with CEP55-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Multinucleated neurons-anhydramnios-renal dysplasia-cerebellar hypoplasia-hydranencephaly syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Dec 23, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.79

CADD

Benign

5.8

DANN

Benign

0.67

DEOGEN2

Benign

0.0013

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.035

LIST_S2

Benign

0.51

M_CAP

Benign

0.0050

MetaRNN

Benign

0.0095

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.71

MutationTaster

Benign

1.0

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.19

REVEL

Benign

0.0050

Sift

Benign

0.25

Sift4G

Benign

0.21

Polyphen

0.0010

Vest4

0.067

MVP

0.12

MPC

0.12

ClinPred

0.0013

GERP RS

-3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.019

gMVP

0.042

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over