rs398122977

Positions:

• chr15-48756099-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001194998.2(CEP152):​c.3149T>C​(p.Leu1050Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000116 in 1,461,828 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as no classification for the single variant (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (1 hom.)
• Consequence: CEP152 NM_001194998.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.09

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEP152	NM_001194998.2	c.3149T>C	p.Leu1050Pro	missense_variant	20/27	ENST00000380950.7	NP_001181927.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEP152	ENST00000380950.7	c.3149T>C	p.Leu1050Pro	missense_variant	20/27	1	NM_001194998.2	ENSP00000370337	A2
CEP152	ENST00000399334.7	c.3149T>C	p.Leu1050Pro	missense_variant	20/26	1		ENSP00000382271	P2
CEP152	ENST00000325747.9	c.2870T>C	p.Leu957Pro	missense_variant	19/25	1		ENSP00000321000	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 249478 Hom.: 0 AF XY: 0.0000296 AC XY: 4 AN XY: 135350

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461828 Hom.: 1 Cov.: 32 AF XY: 0.0000165 AC XY: 12 AN XY: 727218

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;.;.
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.044
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.77	T;T;T
M_CAP	Uncertain	0.086	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	2.0	M;M;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.6	D;D;D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.013	D;T;D
Polyphen		1.0	D;.;D
Vest4		0.90
MutPred		0.75		Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);.;
MVP		0.88
MPC		0.47
ClinPred		0.85	D
GERP RS		5.3
Varity_R		0.75
gMVP		0.73

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: rs398122977; hg19: chr15-49048296;