15-48805535-CTTTTTTTTT-CTTTTTTTT

Variant names:

• chr15-48805535-CT-C
• rs372967874
• NM_001194998.2:c.87+27delA

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+27delA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0723 in 1,138,270 control chromosomes in the GnomAD database, including 31 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.015 (20 hom., cov: 26)
  • Exomes 𝑓: 0.079 (11 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-CT-C is Benign according to our data. Variant chr15-48805535-CT-C is described in ClinVar as Benign. ClinVar VariationId is 1230136.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0146 (1622/111450) while in subpopulation AFR AF = 0.0427 (1410/33046). AF 95% confidence interval is 0.0408. There are 20 homozygotes in GnomAd4. There are 763 alleles in the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 20 AR gene

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.0145 AC: 1621 AN: 111436 Hom.: 20 Cov.: 26

Gnomad AFR AF: 0.0427

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00444

Gnomad ASJ AF: 0.00272

Gnomad EAS AF: 0.000238

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00444

Gnomad MID AF: 0.00435

Gnomad NFE AF: 0.00230

Gnomad OTH AF: 0.00683

GnomAD2 exomes AF: 0.128 AC: 12549 AN: 98152 AF XY: 0.129

Gnomad AFR exome AF: 0.180

Gnomad AMR exome AF: 0.0868

Gnomad ASJ exome AF: 0.0968

Gnomad EAS exome AF: 0.0522

Gnomad FIN exome AF: 0.178

Gnomad NFE exome AF: 0.149

Gnomad OTH exome AF: 0.127

GnomAD4 exome AF: 0.0785 AC: 80651 AN: 1026820 Hom.: 11 Cov.: 24 AF XY: 0.0787 AC XY: 40387 AN XY: 512950

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

African (AFR) AF: 0.118 AC: 2797 AN: 23688

American (AMR) AF: 0.0574 AC: 1766 AN: 30768

Ashkenazi Jewish (ASJ) AF: 0.0761 AC: 1382 AN: 18166

East Asian (EAS) AF: 0.0399 AC: 1172 AN: 29382

South Asian (SAS) AF: 0.0673 AC: 4225 AN: 62788

European-Finnish (FIN) AF: 0.0991 AC: 3086 AN: 31140

Middle Eastern (MID) AF: 0.0726 AC: 276 AN: 3802

European-Non Finnish (NFE) AF: 0.0797 AC: 62559 AN: 784784

Other (OTH) AF: 0.0801 AC: 3388 AN: 42302

⚠️ 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: 0.0146 AC: 1622 AN: 111450 Hom.: 20 Cov.: 26 AF XY: 0.0141 AC XY: 763 AN XY: 54110

African (AFR) AF: 0.0427 AC: 1410 AN: 33046

American (AMR) AF: 0.00444 AC: 50 AN: 11272

Ashkenazi Jewish (ASJ) AF: 0.00272 AC: 6 AN: 2208

East Asian (EAS) AF: 0.000239 AC: 1 AN: 4192

South Asian (SAS) AF: 0.000833 AC: 3 AN: 3602

European-Finnish (FIN) AF: 0.00444 AC: 29 AN: 6528

Middle Eastern (MID) AF: 0.00952 AC: 2 AN: 210

European-Non Finnish (NFE) AF: 0.00230 AC: 111 AN: 48328

Other (OTH) AF: 0.00678 AC: 10 AN: 1476

Alfa AF: 0.0489 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 24, 2019

GeneDx

Significance: Benign

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		0.18
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;