Genetic Variant CCDC146:p.Glu52Val (chr7-77167823-A-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_020879.3(CCDC146):c.155A>T(p.Glu52Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000131 in 152,286 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 35)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CCDC146
NM_020879.3 missense, splice_region

Scores

Splicing: ADA: 0.9999

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.08

Variant links:

Genes affected

CCDC146 (HGNC:29296): (coiled-coil domain containing 146) Located in centriole. [provided by Alliance of Genome Resources, Apr 2022]

CCDC146 links:

ENSG00000259628 (HGNC:):

ENSG00000259628 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC146	NM_020879.3 link	c.155A>T	p.Glu52Val	missense_variant, splice_region_variant	Exon 2 of 19	ENST00000285871.5	NP_065930.2	Q8IYE0-1Q96MS1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CCDC146	ENST00000285871.5 link	c.155A>T	p.Glu52Val	missense_variant, splice_region_variant	Exon 2 of 19	1	NM_020879.3	ENSP00000285871.4	Q8IYE0-1
CCDC146	ENST00000415750.5 link	c.155A>T	p.Glu52Val	missense_variant, splice_region_variant	Exon 2 of 5	4		ENSP00000388649.1	C9JRR4
ENSG00000259628	ENST00000459742.1 link	n.224A>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152286

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000137

AC:

AN:

1458878

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725678

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000226

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152286

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.155A>T (p.E52V) alteration is located in exon 2 (coding exon 1) of the CCDC146 gene. This alteration results from a A to T substitution at nucleotide position 155, causing the glutamic acid (E) at amino acid position 52 to be replaced by a valine (V). 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

0.45

BayesDel_addAF

Uncertain

0.078

BayesDel_noAF

Benign

-0.13

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.053

.;T

Eigen

Benign

0.11

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.54

T;T

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.23

T;T

MetaSVM

Uncertain

0.030

MutationAssessor

Uncertain

2.4

.;M

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-4.7

D;D

REVEL

Uncertain

0.51

Sift

Uncertain

0.012

D;D

Sift4G

Uncertain

0.0080

D;D

Polyphen

0.98

D;B

Vest4

0.60

MutPred

0.45

Loss of disorder (P = 0.0888);Loss of disorder (P = 0.0888);

MVP

0.57

MPC

0.58

ClinPred

0.95

GERP RS

4.1

Varity_R

0.26

gMVP

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.98

SpliceAI score (max)

0.48

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.47

Position offset: -45

DS_DL_spliceai

0.48

Position offset: 1

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over