rs149478199

Variant names:

• chr15-48741622-G-C
• rs149478199
• NM_001194998.2:c.4072C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001194998.2(CEP152):​c.4072C>G​(p.Gln1358Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000369 in 1,614,074 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (3 hom.)
• Consequence: CEP152 NM_001194998.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 3.91
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039657354).
• BP6: Variant 15-48741622-G-C is Benign according to our data. Variant chr15-48741622-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 158262.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00192 (292/152248) while in subpopulation AFR AF = 0.00662 (275/41548). AF 95% confidence interval is 0.00598. There are 1 homozygotes in GnomAd4. There are 121 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

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.4072C>G	p.Gln1358Glu	missense	Exon 26 of 27	NP_001181927.1	O94986-4
	CEP152	NM_014985.4		c.3904C>G	p.Gln1302Glu	missense	Exon 25 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.4072C>G	p.Gln1358Glu	missense	Exon 26 of 27	ENSP00000370337.2	O94986-4
	CEP152	ENST00000399334.7	TSL:1	c.3904C>G	p.Gln1302Glu	missense	Exon 25 of 26	ENSP00000382271.3	O94986-3
	CEP152	ENST00000325747.9	TSL:1	c.3793C>G	p.Gln1265Glu	missense	Exon 25 of 25	ENSP00000321000.5	O94986-1

Frequencies

GnomAD3 genomes AF: 0.00192 AC: 292 AN: 152130 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00664

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000405 AC: 101 AN: 249398 AF XY: 0.000310

Gnomad AFR exome AF: 0.00601

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000208 AC: 304 AN: 1461826 Hom.: 3 Cov.: 32 AF XY: 0.000182 AC XY: 132 AN XY: 727208

African (AFR) AF: 0.00753 AC: 252 AN: 33480

American (AMR) AF: 0.000246 AC: 11 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111994

Other (OTH) AF: 0.000447 AC: 27 AN: 60394

GnomAD4 genome AF: 0.00192 AC: 292 AN: 152248 Hom.: 1 Cov.: 32 AF XY: 0.00163 AC XY: 121 AN XY: 74444

African (AFR) AF: 0.00662 AC: 275 AN: 41548

American (AMR) AF: 0.000916 AC: 14 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68022

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000296 Hom.: 0

Bravo AF: 0.00195

ESP6500AA AF: 0.00483 AC: 18

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.000463 AC: 56

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	CEP152-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	1	-	Microcephaly 9, primary, autosomal recessive (1)
-	-	1	Seckel syndrome 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	14
DANN	Benign	0.55
DEOGEN2	Benign	0.030	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.43
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.9
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.16
Sift	Benign	0.092	T
Sift4G	Benign	0.090	T
Polyphen		0.073	B
Vest4		0.15
MVP		0.47
MPC		0.068
ClinPred		0.025	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.059
gMVP		0.025
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: rs149478199; hg19: chr15-49033819; COSMIC: COSV107352494;