15-48805535-CTTTTTTTTT-CTTTTTTT

Variant names:

• chr15-48805535-CTT-C
• rs372967874
• NM_001194998.2:c.87+26_87+27delAA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001194998.2(CEP152):​c.87+26_87+27delAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00236 in 1,220,676 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000054 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0026 (0 hom.)
• Consequence: CEP152 NM_001194998.2 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.192
• Publications: 0 publications found

Genes affected

CEP152 (HGNC:29298): (centrosomal protein 152) This gene encodes a protein that is thought to be involved with centrosome function. Mutations in this gene have been associated with primary microcephaly (MCPH4). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2010]

CEP152 Gene-Disease associations (from GenCC):

• microcephaly with or without short stature

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Seckel syndrome 5

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• microcephaly 9, primary, autosomal recessive

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• autosomal recessive primary microcephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Seckel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Variant has high frequency in the AFR (0.00421) population. However there is too low homozygotes in high coverage region: (expected more than 1, got 0).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP152	NM_001194998.2	c.87+26_87+27delAA		intron_variant	Intron 2 of 26	ENST00000380950.7	NP_001181927.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP152	ENST00000380950.7	c.87+26_87+27delAA		intron_variant	Intron 2 of 26	1	NM_001194998.2	ENSP00000370337.2

Frequencies

GnomAD3 genomes AF: 0.0000538 AC: 6 AN: 111476 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000303

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000306

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000620

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00451 AC: 443 AN: 98152 AF XY: 0.00476

Gnomad AFR exome AF: 0.00776

Gnomad AMR exome AF: 0.00295

Gnomad ASJ exome AF: 0.00222

Gnomad EAS exome AF: 0.00123

Gnomad FIN exome AF: 0.00619

Gnomad NFE exome AF: 0.00541

Gnomad OTH exome AF: 0.00485

GnomAD4 exome AF: 0.00260 AC: 2880 AN: 1109200 Hom.: 0 AF XY: 0.00264 AC XY: 1466 AN XY: 555496

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00491 AC: 125 AN: 25456

American (AMR) AF: 0.00317 AC: 101 AN: 31866

Ashkenazi Jewish (ASJ) AF: 0.00437 AC: 85 AN: 19438

East Asian (EAS) AF: 0.00191 AC: 58 AN: 30410

South Asian (SAS) AF: 0.00153 AC: 104 AN: 68078

European-Finnish (FIN) AF: 0.00552 AC: 180 AN: 32620

Middle Eastern (MID) AF: 0.00125 AC: 5 AN: 4008

European-Non Finnish (NFE) AF: 0.00246 AC: 2092 AN: 851918

Other (OTH) AF: 0.00286 AC: 130 AN: 45406

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000538 AC: 6 AN: 111476 Hom.: 0 Cov.: 0 AF XY: 0.0000555 AC XY: 3 AN XY: 54072

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000303 AC: 1 AN: 32998

American (AMR) AF: 0.00 AC: 0 AN: 11270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2210

East Asian (EAS) AF: 0.00 AC: 0 AN: 4204

South Asian (SAS) AF: 0.00 AC: 0 AN: 3620

European-Finnish (FIN) AF: 0.000306 AC: 2 AN: 6536

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 230

European-Non Finnish (NFE) AF: 0.0000620 AC: 3 AN: 48356

Other (OTH) AF: 0.00 AC: 0 AN: 1464

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000002), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00279 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.19
Mutation Taster		=100/0	polymorphism

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: rs372967874; hg19: chr15-49097732;