NM_033395.2:c.7668G>T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_033395.2(CEP295):c.7668G>T(p.Arg2556Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000215 in 1,394,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

CEP295
NM_033395.2 missense, splice_region

Scores

Splicing: ADA: 0.8701

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0260

Publications

0 publications found

Variant links:

Genes affected

CEP295 (HGNC:29366): (centrosomal protein 295) Enables microtubule binding activity. Involved in several processes, including centriole replication; positive regulation of protein acetylation; and regulation of centrosome duplication. Located in cytosol; microtubule cytoskeleton; and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

CEP295 links:

TAF1D (HGNC:28759): (TATA-box binding protein associated factor, RNA polymerase I subunit D) TAF1D is a member of the SL1 complex, which includes TBP (MIM 600075) and TAF1A (MIM 604903), TAF1B (MIM 604904), and TAF1C (MIM 604905), and plays a role in RNA polymerase I transcription (Wang et al., 2004 [PubMed 15520167]; Gorski et al., 2007 [PubMed 17318177]).[supplied by OMIM, Jun 2009]

TAF1D links:

ENSG00000279696 (HGNC:):

ENSG00000279696 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16086787).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP295	NM_033395.2 link	c.7668G>T	p.Arg2556Ser	missense_variant, splice_region_variant	Exon 29 of 30	ENST00000325212.11	NP_203753.1	Q9C0D2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP295	ENST00000325212.11 link	c.7668G>T	p.Arg2556Ser	missense_variant, splice_region_variant	Exon 29 of 30	2	NM_033395.2	ENSP00000316681.6		Q9C0D2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000652

AC:

AN:

153288

AF XY:

0.0000123

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000233

GnomAD4 exome

AF:

0.00000215

AC:

AN:

1394598

Hom.:

Cov.:

AF XY:

0.00000291

AC XY:

AN XY:

687980

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31226

American (AMR)

AF:

0.00

AC:

AN:

35102

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25048

East Asian (EAS)

AF:

0.00

AC:

AN:

35690

South Asian (SAS)

AF:

0.00

AC:

AN:

78610

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49138

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5656

European-Non Finnish (NFE)

AF:

0.00000186

AC:

AN:

1076382

Other (OTH)

AF:

0.0000173

AC:

AN:

57746

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000251

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 03, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.7668G>T (p.R2556S) alteration is located in exon 29 (coding exon 28) of the CEP295 gene. This alteration results from a G to T substitution at nucleotide position 7668, causing the arginine (R) at amino acid position 2556 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.024

T;.;T

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.80

T;T;T

M_CAP

Benign

0.053

MetaRNN

Benign

0.16

T;T;T

MetaSVM

Benign

-1.0

PhyloP100

0.026

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.8

N;D;D

REVEL

Benign

0.23

Sift

Uncertain

0.012

D;D;D

Sift4G

Uncertain

0.013

D;D;D

Polyphen

0.83

P;P;.

Vest4

0.54

MutPred

0.20

Loss of MoRF binding (P = 0.0286);.;.;

MVP

0.014

MPC

0.10

ClinPred

0.42

GERP RS

-5.2

Varity_R

0.14

gMVP

0.19

Mutation Taster

=75/25

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.87

dbscSNV1_RF

Benign

0.47

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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NM_033395.2:c.7668G>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over