15-48756370-A-T

Variant names:

• chr15-48756370-A-T
• NM_001194998.2:c.2878T>A
• CEP152 p.Trp960Arg

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001194998.2(CEP152):​c.2878T>A​(p.Trp960Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CEP152 NM_001194998.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.71
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.798

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001194998.2. 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
	CEP152	NM_001194998.2	MANE Select	c.2878T>A	p.Trp960Arg	missense	Exon 20 of 27	NP_001181927.1	O94986-4
	CEP152	NM_014985.4		c.2878T>A	p.Trp960Arg	missense	Exon 20 of 26	NP_055800.2	O94986-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP152	ENST00000380950.7	TSL:1 MANE Select	c.2878T>A	p.Trp960Arg	missense	Exon 20 of 27	ENSP00000370337.2	O94986-4
	CEP152	ENST00000399334.7	TSL:1	c.2878T>A	p.Trp960Arg	missense	Exon 20 of 26	ENSP00000382271.3	O94986-3
	CEP152	ENST00000325747.9	TSL:1	c.2599T>A	p.Trp867Arg	missense	Exon 19 of 25	ENSP00000321000.5	O94986-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.74	T
M_CAP	Uncertain	0.088	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		6.7
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-8.6	D
REVEL	Uncertain	0.44
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Varity_R		0.94
gMVP		0.61

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr15-49048567;