chr15-48738198-C-T

Variant names:

• chr15-48738198-C-T
• rs531632293
• NM_001194998.2:c.*51G>A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001194998.2(CEP152):​c.*51G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,532,998 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (6 hom.)
• Consequence: CEP152 NM_001194998.2 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.575

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00131 (200/152250) while in subpopulation NFE AF= 0.00229 (156/68016). AF 95% confidence interval is 0.002. There are 2 homozygotes in gnomad4. There are 89 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP152	NM_001194998.2	c.*51G>A		3_prime_UTR_variant	Exon 27 of 27	ENST00000380950.7	NP_001181927.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP152	ENST00000380950	c.*51G>A		3_prime_UTR_variant	Exon 27 of 27	1	NM_001194998.2	ENSP00000370337.2
CEP152	ENST00000399334	c.*51G>A		3_prime_UTR_variant	Exon 26 of 26	1		ENSP00000382271.3
CEP152	ENST00000561245.1	n.142+3433G>A		intron_variant	Intron 2 of 3	2		ENSP00000453591.1

Frequencies

GnomAD3 genomes AF: 0.00131 AC: 200 AN: 152132 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00229

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000809 AC: 128 AN: 158182 Hom.: 0 AF XY: 0.000801 AC XY: 68 AN XY: 84852

Gnomad AFR exome AF: 0.000316

Gnomad AMR exome AF: 0.000258

Gnomad ASJ exome AF: 0.000130

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000486

Gnomad FIN exome AF: 0.000201

Gnomad NFE exome AF: 0.00170

Gnomad OTH exome AF: 0.000236

GnomAD4 exome AF: 0.00104 AC: 1433 AN: 1380748 Hom.: 6 Cov.: 30 AF XY: 0.00107 AC XY: 729 AN XY: 679990

Gnomad4 AFR exome AF: 0.0000984

Gnomad4 AMR exome AF: 0.000208

Gnomad4 ASJ exome AF: 0.0000412

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000131

Gnomad4 FIN exome AF: 0.000459

Gnomad4 NFE exome AF: 0.00127

Gnomad4 OTH exome AF: 0.000701

GnomAD4 genome AF: 0.00131 AC: 200 AN: 152250 Hom.: 2 Cov.: 32 AF XY: 0.00120 AC XY: 89 AN XY: 74466

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00229

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00319 Hom.: 1

Bravo AF: 0.00104

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Microcephaly 9, primary, autosomal recessive Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Seckel syndrome 5 Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.0
DANN	Benign	0.52

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

Publications

LitVar

Other links and lift over

dbSNP: rs531632293; hg19: chr15-49030395;