chr15-48805535-C-CTT

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001194998.2(CEP152):​c.87+26_87+27dupAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00815 in 1,228,752 control chromosomes in the GnomAD database, including 27 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.012 (22 hom., cov: 26)
  • Exomes 𝑓: 0.0078 (5 hom.)
• Consequence: CEP152 NM_001194998.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.181
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 15-48805535-C-CTT is Benign according to our data. Variant chr15-48805535-C-CTT is described in ClinVar as Benign. ClinVar VariationId is 1270486.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0119 (1322/111476) while in subpopulation AMR AF = 0.0325 (366/11268). AF 95% confidence interval is 0.0297. There are 22 homozygotes in GnomAd4. There are 667 alleles in the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 AR gene

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.0118 AC: 1318 AN: 111460 Hom.: 21 Cov.: 26

Gnomad AFR AF: 0.0226

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0324

Gnomad ASJ AF: 0.000452

Gnomad EAS AF: 0.0186

Gnomad SAS AF: 0.00470

Gnomad FIN AF: 0.00214

Gnomad MID AF: 0.00435

Gnomad NFE AF: 0.00174

Gnomad OTH AF: 0.00956

GnomAD2 exomes AF: 0.0220 AC: 2159 AN: 98152 AF XY: 0.0200

Gnomad AFR exome AF: 0.0245

Gnomad AMR exome AF: 0.0610

Gnomad ASJ exome AF: 0.00505

Gnomad EAS exome AF: 0.0502

Gnomad FIN exome AF: 0.00928

Gnomad NFE exome AF: 0.00933

Gnomad OTH exome AF: 0.0162

GnomAD4 exome AF: 0.00778 AC: 8693 AN: 1117276 Hom.: 5 Cov.: 24 AF XY: 0.00774 AC XY: 4329 AN XY: 559238

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

African (AFR) AF: 0.0221 AC: 565 AN: 25510

American (AMR) AF: 0.0410 AC: 1291 AN: 31520

Ashkenazi Jewish (ASJ) AF: 0.00352 AC: 69 AN: 19626

East Asian (EAS) AF: 0.0433 AC: 1285 AN: 29682

South Asian (SAS) AF: 0.0120 AC: 810 AN: 67712

European-Finnish (FIN) AF: 0.00967 AC: 318 AN: 32898

Middle Eastern (MID) AF: 0.00593 AC: 24 AN: 4046

European-Non Finnish (NFE) AF: 0.00453 AC: 3902 AN: 860592

Other (OTH) AF: 0.00939 AC: 429 AN: 45690

⚠️ 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: 0.0119 AC: 1322 AN: 111476 Hom.: 22 Cov.: 26 AF XY: 0.0123 AC XY: 667 AN XY: 54106

African (AFR) AF: 0.0226 AC: 747 AN: 33044

American (AMR) AF: 0.0325 AC: 366 AN: 11268

Ashkenazi Jewish (ASJ) AF: 0.000452 AC: 1 AN: 2210

East Asian (EAS) AF: 0.0184 AC: 77 AN: 4192

South Asian (SAS) AF: 0.00472 AC: 17 AN: 3600

European-Finnish (FIN) AF: 0.00214 AC: 14 AN: 6540

Middle Eastern (MID) AF: 0.00476 AC: 1 AN: 210

European-Non Finnish (NFE) AF: 0.00174 AC: 84 AN: 48348

Other (OTH) AF: 0.0102 AC: 15 AN: 1476

Alfa AF: 0.00469 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 10, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.18
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs372967874; hg19: chr15-49097732;