NM_001194998.2:c.4094-9A>T

Variant names:

• chr15-48739297-T-A
• rs80090788
• NM_001194998.2:c.4094-9A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001194998.2(CEP152):​c.4094-9A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00066 in 1,596,432 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00035 (4 hom.)
• Consequence: CEP152 NM_001194998.2 intron
• Scores: Splicing: ADA: 0.00002915
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0140
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 15-48739297-T-A is Benign according to our data. Variant chr15-48739297-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95654.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00357 (544/152236) while in subpopulation AFR AF = 0.0127 (527/41542). AF 95% confidence interval is 0.0118. There are 3 homozygotes in GnomAd4. There are 245 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 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.4094-9A>T		intron	N/A	NP_001181927.1
	CEP152	NM_014985.4		c.3926-9A>T		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.4094-9A>T		intron	N/A	ENSP00000370337.2
	CEP152	ENST00000399334.7	TSL:1	c.3926-9A>T		intron	N/A	ENSP00000382271.3
	CEP152	ENST00000561245.1	TSL:2	n.142+2334A>T		intron	N/A	ENSP00000453591.1

Frequencies

GnomAD3 genomes AF: 0.00358 AC: 544 AN: 152118 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0127

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

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: 0.00192

GnomAD2 exomes AF: 0.000859 AC: 201 AN: 233860 AF XY: 0.000654

Gnomad AFR exome AF: 0.0126

Gnomad AMR exome AF: 0.000224

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000934

Gnomad OTH exome AF: 0.000176

GnomAD4 exome AF: 0.000353 AC: 510 AN: 1444196 Hom.: 4 Cov.: 31 AF XY: 0.000293 AC XY: 210 AN XY: 717526

African (AFR) AF: 0.0131 AC: 429 AN: 32734

American (AMR) AF: 0.000364 AC: 15 AN: 41180

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25512

East Asian (EAS) AF: 0.00 AC: 0 AN: 39404

South Asian (SAS) AF: 0.0000247 AC: 2 AN: 80870

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52554

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5686

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1106624

Other (OTH) AF: 0.000855 AC: 51 AN: 59632

GnomAD4 genome AF: 0.00357 AC: 544 AN: 152236 Hom.: 3 Cov.: 32 AF XY: 0.00329 AC XY: 245 AN XY: 74432

African (AFR) AF: 0.0127 AC: 527 AN: 41542

American (AMR) AF: 0.000785 AC: 12 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68008

Other (OTH) AF: 0.00190 AC: 4 AN: 2108

Alfa AF: 0.00109 Hom.: 0

Bravo AF: 0.00397

Asia WGS AF: 0.000578 AC: 2 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Microcephaly 9, primary, autosomal recessive (1)
-	-	1	Seckel syndrome 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	8.8
DANN	Benign	0.86
PhyloP100		-0.014
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000029
dbscSNV1_RF	Benign	0.16
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: rs80090788; hg19: chr15-49031494;