11-93679422-G-A

Variant names:

• chr11-93679422-G-A
• rs934311260
• NM_033395.2:c.635G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_033395.2(CEP295):​c.635G>A​(p.Arg212His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,396,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R212C) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: CEP295 NM_033395.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.06
• Publications: 1 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.020623088).
• BP6: Variant 11-93679422-G-A is Benign according to our data. Variant chr11-93679422-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2330572.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP295	NM_033395.2	c.635G>A	p.Arg212His	missense_variant	Exon 7 of 30	ENST00000325212.11	NP_203753.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP295	ENST00000325212.11	c.635G>A	p.Arg212His	missense_variant	Exon 7 of 30	2	NM_033395.2	ENSP00000316681.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000136 AC: 19 AN: 1396710 Hom.: 0 Cov.: 30 AF XY: 0.0000189 AC XY: 13 AN XY: 688824

African (AFR) AF: 0.0000317 AC: 1 AN: 31500

American (AMR) AF: 0.00 AC: 0 AN: 35464

Ashkenazi Jewish (ASJ) AF: 0.0000399 AC: 1 AN: 25088

East Asian (EAS) AF: 0.0000281 AC: 1 AN: 35638

South Asian (SAS) AF: 0.00 AC: 0 AN: 78742

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49236

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5690

European-Non Finnish (NFE) AF: 0.0000139 AC: 15 AN: 1077450

Other (OTH) AF: 0.0000173 AC: 1 AN: 57902

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Dec 01, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	16
DANN	Benign	0.24
DEOGEN2	Benign	0.0064	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.021	T
MetaSVM	Benign	-0.97	T
PhyloP100		1.1
PrimateAI	Benign	0.24	T
PROVEAN	Benign	2.4	N
REVEL	Benign	0.028
Sift	Benign	1.0	T
Sift4G	Benign	0.62	T
Polyphen		0.0010	B
Vest4		0.083
MutPred		0.33		Gain of methylation at K207 (P = 0.0713);
MVP		0.014
MPC		0.10
ClinPred		0.17	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.031
gMVP		0.11
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs934311260; hg19: chr11-93412588;