rs141458677

Variant names:

• chr10-93503185-C-T
• rs141458677
• NM_018131.5:c.256C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_018131.5(CEP55):​c.256C>T​(p.Arg86*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000449 in 1,613,690 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00048 (0 hom.)
• Consequence: CEP55 NM_018131.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 0.00600
• Publications: 11 publications found

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 Gene-Disease associations (from GenCC):

• multinucleated neurons-anhydramnios-renal dysplasia-cerebellar hypoplasia-hydranencephaly syndrome

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• complex neurodevelopmental disorder

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 10-93503185-C-T is Pathogenic according to our data. Variant chr10-93503185-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 437875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018131.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP55	NM_018131.5	MANE Select	c.256C>T	p.Arg86*	stop_gained	Exon 3 of 9	NP_060601.4
	CEP55	NM_001127182.2		c.256C>T	p.Arg86*	stop_gained	Exon 3 of 9	NP_001120654.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP55	ENST00000371485.8	TSL:1 MANE Select	c.256C>T	p.Arg86*	stop_gained	Exon 3 of 9	ENSP00000360540.3

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152062 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000282 AC: 71 AN: 251356 AF XY: 0.000228

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000378

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000478 AC: 698 AN: 1461628 Hom.: 0 Cov.: 31 AF XY: 0.000446 AC XY: 324 AN XY: 727140

African (AFR) AF: 0.0000896 AC: 3 AN: 33478

American (AMR) AF: 0.000470 AC: 21 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39688

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.000262 AC: 14 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000576 AC: 640 AN: 1111792

Other (OTH) AF: 0.000298 AC: 18 AN: 60386

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152062 Hom.: 0 Cov.: 33 AF XY: 0.000202 AC XY: 15 AN XY: 74252

African (AFR) AF: 0.0000725 AC: 3 AN: 41400

American (AMR) AF: 0.000131 AC: 2 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68030

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000355 Hom.: 0

Bravo AF: 0.000227

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000379 AC: 46

EpiCase AF: 0.000763

EpiControl AF: 0.000296

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Multinucleated neurons-anhydramnios-renal dysplasia-cerebellar hypoplasia-hydranencephaly syndrome (4)
2	-	-	not provided (2)
1	-	-	CEP55-related disorder (1)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.38	N
PhyloP100		0.0060
Vest4		0.83
GERP RS		2.4
Mutation Taster		=32/168	disease causing (ClinVar)

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: rs141458677; hg19: chr10-95262942; COSMIC: COSV65184705; COSMIC: COSV65184705;