rs369980055

Variant names:

• chr15-48744294-C-T
• rs369980055
• NM_001194998.2:c.3781G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001194998.2(CEP152):​c.3781G>A​(p.Gly1261Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CEP152 NM_001194998.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.879
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04275629).

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.3781G>A	p.Gly1261Arg	missense	Exon 24 of 27	NP_001181927.1
	CEP152	NM_014985.4		c.3613G>A	p.Gly1205Arg	missense	Exon 23 of 26	NP_055800.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP152	ENST00000380950.7	TSL:1 MANE Select	c.3781G>A	p.Gly1261Arg	missense	Exon 24 of 27	ENSP00000370337.2
	CEP152	ENST00000399334.7	TSL:1	c.3613G>A	p.Gly1205Arg	missense	Exon 23 of 26	ENSP00000382271.3
	CEP152	ENST00000325747.9	TSL:1	c.3502G>A	p.Gly1168Arg	missense	Exon 23 of 25	ENSP00000321000.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 249516 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461748 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727170

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111948

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000123 AC: 1

ExAC AF: 0.0000166 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	Microcephaly 9, primary, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	10
DANN	Benign	0.38
DEOGEN2	Benign	0.00083	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N
PhyloP100		0.88
PrimateAI	Benign	0.24	T
PROVEAN	Benign	1.9	N
REVEL	Benign	0.046
Sift	Benign	0.54	T
Sift4G	Benign	0.53	T
Polyphen		0.0010	B
Vest4		0.15
MVP		0.48
MPC		0.074
ClinPred		0.031	T
GERP RS		0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.090
gMVP		0.047
Mutation Taster		=94/6	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: rs369980055; hg19: chr15-49036491;