15-48752341-C-G

Variant names:

• chr15-48752341-C-G
• rs2306187
• NM_001194998.2:c.3466+8G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001194998.2(CEP152):​c.3466+8G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 1,613,764 control chromosomes in the GnomAD database, including 28,309 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (7186 hom., cov: 32)
  • Exomes 𝑓: 0.15 (21123 hom.)
• Consequence: CEP152 NM_001194998.2 splice_region, intron
• Scores: Splicing: ADA: 0.000004609
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.533
• Publications: 13 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 15-48752341-C-G is Benign according to our data. Variant chr15-48752341-C-G is described in ClinVar as Benign. ClinVar VariationId is 95653.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.508 is higher than 0.05.

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.3466+8G>C		splice_region intron	N/A	NP_001181927.1
	CEP152	NM_014985.4		c.3466+8G>C		splice_region intron	N/A	NP_055800.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP152	ENST00000380950.7	TSL:1 MANE Select	c.3466+8G>C		splice_region intron	N/A	ENSP00000370337.2
	CEP152	ENST00000399334.7	TSL:1	c.3466+8G>C		splice_region intron	N/A	ENSP00000382271.3
	CEP152	ENST00000325747.9	TSL:1	c.3187+8G>C		splice_region intron	N/A	ENSP00000321000.5

Frequencies

GnomAD3 genomes AF: 0.252 AC: 38280 AN: 151916 Hom.: 7161 Cov.: 32

Gnomad AFR AF: 0.514

Gnomad AMI AF: 0.197

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.0819

Gnomad EAS AF: 0.471

Gnomad SAS AF: 0.155

Gnomad FIN AF: 0.142

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.126

Gnomad OTH AF: 0.207

GnomAD2 exomes AF: 0.194 AC: 48442 AN: 249462 AF XY: 0.182

Gnomad AFR exome AF: 0.527

Gnomad AMR exome AF: 0.236

Gnomad ASJ exome AF: 0.0827

Gnomad EAS exome AF: 0.491

Gnomad FIN exome AF: 0.140

Gnomad NFE exome AF: 0.128

Gnomad OTH exome AF: 0.142

GnomAD4 exome AF: 0.147 AC: 214448 AN: 1461728 Hom.: 21123 Cov.: 32 AF XY: 0.144 AC XY: 104944 AN XY: 727164

African (AFR) AF: 0.530 AC: 17745 AN: 33472

American (AMR) AF: 0.234 AC: 10470 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0797 AC: 2082 AN: 26136

East Asian (EAS) AF: 0.446 AC: 17715 AN: 39692

South Asian (SAS) AF: 0.135 AC: 11609 AN: 86252

European-Finnish (FIN) AF: 0.138 AC: 7361 AN: 53402

Middle Eastern (MID) AF: 0.127 AC: 720 AN: 5688

European-Non Finnish (NFE) AF: 0.123 AC: 136830 AN: 1111986

Other (OTH) AF: 0.164 AC: 9916 AN: 60384

GnomAD4 genome AF: 0.252 AC: 38338 AN: 152036 Hom.: 7186 Cov.: 32 AF XY: 0.251 AC XY: 18665 AN XY: 74316

African (AFR) AF: 0.514 AC: 21307 AN: 41458

American (AMR) AF: 0.189 AC: 2892 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0819 AC: 284 AN: 3466

East Asian (EAS) AF: 0.472 AC: 2433 AN: 5160

South Asian (SAS) AF: 0.154 AC: 740 AN: 4818

European-Finnish (FIN) AF: 0.142 AC: 1503 AN: 10558

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.126 AC: 8541 AN: 67964

Other (OTH) AF: 0.205 AC: 432 AN: 2108

Alfa AF: 0.113 Hom.: 434

Bravo AF: 0.274

Asia WGS AF: 0.296 AC: 1028 AN: 3478

EpiCase AF: 0.125

EpiControl AF: 0.123

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	Microcephaly 9, primary, autosomal recessive (2)
-	-	2	not provided (2)
-	-	2	Seckel syndrome 5 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	3.7
DANN	Benign	0.42
PhyloP100		0.53
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000046
dbscSNV1_RF	Benign	0.0
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: rs2306187; hg19: chr15-49044538; COSMIC: COSV57857859;