10-93503308-G-A

Variant names:

• chr10-93503308-G-A
• rs199894468
• NM_018131.5:c.379G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_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. 16/23 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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -0.189

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]

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009529173).
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 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 GnomAdExome4. There are 461 alleles in the male GnomAdExome4 subpopulation. Median coverage is 35. This position FAILED quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP55	NM_018131.5	c.379G>A	p.Val127Ile	missense_variant	Exon 3 of 9	ENST00000371485.8	NP_060601.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP55	ENST00000371485.8	c.379G>A	p.Val127Ile	missense_variant	Exon 3 of 9	1	NM_018131.5	ENSP00000360540.3

Frequencies

GnomAD3 genomes AF: 0.000473 AC: 72 AN: 152164 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.000569 AC: 143 AN: 251432 AF XY: 0.000655

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 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.: 0 Cov.: 35 AF XY: 0.000634 AC XY: 461 AN XY: 727218

Gnomad4 AFR exome AF: 0.000209 AC: 7 AN: 33478

Gnomad4 AMR exome AF: 0.000917 AC: 41 AN: 44722

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26132

Gnomad4 EAS exome AF: 0.000277 AC: 11 AN: 39694

Gnomad4 SAS exome AF: 0.0000812 AC: 7 AN: 86256

Gnomad4 FIN exome AF: 0.000131 AC: 7 AN: 53420

Gnomad4 NFE exome AF: 0.000742 AC: 825 AN: 1111978

Gnomad4 Remaining exome AF: 0.000679 AC: 41 AN: 60392

GnomAD4 genome AF: 0.000473 AC: 72 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.000389 AC XY: 29 AN XY: 74462

Gnomad4 AFR AF: 0.000337 AC: 0.000336862 AN: 0.000336862

Gnomad4 AMR AF: 0.000523 AC: 0.000523013 AN: 0.000523013

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.000193 AC: 0.000192753 AN: 0.000192753

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000706 AC: 0.000705758 AN: 0.000705758

Gnomad4 OTH AF: 0.000473 AC: 0.00047259 AN: 0.00047259

Alfa AF: 0.000628 Hom.: 0

Bravo AF: 0.000612

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000535 AC: 65

EpiCase AF: 0.00104

EpiControl AF: 0.00136

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

May 05, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Apr 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. ClinVar contains an entry for this variant (Variation ID: 2049472). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". 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

Dec 23, 2019

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.8
DANN	Benign	0.67
DEOGEN2	Benign	0.0013	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.0095	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.71	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.0050
Sift	Benign	0.25	T
Sift4G	Benign	0.21	T
Polyphen		0.0010	B
Vest4		0.067
MVP		0.12
MPC		0.12
ClinPred		0.0013	T
GERP RS		-3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.019
gMVP		0.042
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs199894468; hg19: chr10-95263065; COSMIC: COSV65185835; COSMIC: COSV65185835;