11-57659654-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_006831.3(CLP1):c.178G>T(p.Gly60Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000088 in 1,614,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000086 ( 0 hom. )

Consequence

CLP1
NM_006831.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 9.65

Variant links:

Genes affected

CLP1 (HGNC:16999): (cleavage factor polyribonucleotide kinase subunit 1) This gene encodes a member of the Clp1 family. The encoded protein is a multifunctional kinase which is a component of the tRNA splicing endonuclease complex and a component of the pre-mRNA cleavage complex II. This protein is implicated in tRNA, mRNA, and siRNA maturation. Mutations in this gene are associated with pontocerebellar hypoplasia type 10 (PCH10). Alternatively splice transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2014]

CLP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.83

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLP1	NM_006831.3 link	c.178G>T	p.Gly60Cys	missense_variant	Exon 2 of 3	ENST00000533682.2	NP_006822.1	Q92989-1
CLP1	NM_001142597.2 link	c.178G>T	p.Gly60Cys	missense_variant	Exon 2 of 3		NP_001136069.1	Q92989-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLP1	ENST00000533682.2 link	c.178G>T	p.Gly60Cys	missense_variant	Exon 2 of 3	1	NM_006831.3	ENSP00000434995.1		Q92989-1

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000111

AC:

AN:

251482

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000237

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000862

AC:

126

AN:

1461888

Hom.:

Cov.:

AF XY:

0.0000880

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

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:

0.000109

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000105

AC:

AN:

152130

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000664

Hom.:

Bravo

AF:

0.000102

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

May 11, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.178G>T (p.G60C) alteration is located in exon 2 (coding exon 1) of the CLP1 gene. This alteration results from a G to T substitution at nucleotide position 178, causing the glycine (G) at amino acid position 60 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Pontocerebellar hypoplasia type 10

Uncertain:1

Jun 30, 2020

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Uncertain

0.050

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

T;T;T;.;T;.

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.95

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

D;D;.;D;D;D

M_CAP

Benign

0.036

MetaRNN

Pathogenic

0.83

D;D;D;D;D;D

MetaSVM

Uncertain

-0.15

MutationAssessor

Uncertain

2.6

.;.;M;.;M;M

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-7.6

D;D;D;D;D;D

REVEL

Pathogenic

0.65

Sift

Uncertain

0.0010

D;D;D;D;D;D

Sift4G

Uncertain

0.011

D;D;D;D;D;D

Polyphen

1.0

.;.;D;.;D;D

Vest4

0.84, 0.84, 0.86, 0.83

MVP

0.68

MPC

1.6

ClinPred

0.89

GERP RS

5.5

Varity_R

0.87

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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