10-93519809-T-C

Variant names:

• chr10-93519809-T-C
• rs1002854345
• NM_018131.5:c.1191+2T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_018131.5(CEP55):​c.1191+2T>C variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000274 in 1,461,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CEP55 NM_018131.5 splice_donor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.79
• Publications: 1 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• complex neurodevelopmental disorder

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.090322584 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-93519809-T-C is Pathogenic according to our data. Variant chr10-93519809-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 520544.Status of the report is criteria_provided_single_submitter, 1 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP55	NM_018131.5	MANE Select	c.1191+2T>C		splice_donor intron	N/A	NP_060601.4
	CEP55	NM_001127182.2		c.1191+2T>C		splice_donor intron	N/A	NP_001120654.2	Q53EZ4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP55	ENST00000371485.8	TSL:1 MANE Select	c.1191+2T>C		splice_donor intron	N/A	ENSP00000360540.3	Q53EZ4-1
	CEP55	ENST00000897343.1		c.1191+2T>C		splice_donor intron	N/A	ENSP00000567402.1
	CEP55	ENST00000912346.1		c.1191+2T>C		splice_donor intron	N/A	ENSP00000582405.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461676 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727148

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53256

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

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111984

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	27
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		6.8
GERP RS		4.8
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.86
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1002854345; hg19: chr10-95279566; COSMIC: COSV65185366; COSMIC: COSV65185366;