11-57659708-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_006831.3(CLP1):c.232C>T(p.Arg78Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000366 in 1,613,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: CLP1 NM_006831.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.40

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CLP1
• BP4: Computational evidence support a benign effect (MetaRNN=0.26025015).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLP1	NM_006831.3	c.232C>T	p.Arg78Cys	missense_variant	2/3	ENST00000533682.2
CLP1	NM_001142597.2	c.232C>T	p.Arg78Cys	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLP1	ENST00000533682.2	c.232C>T	p.Arg78Cys	missense_variant	2/3	1	NM_006831.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 152084 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000795 AC: 20 AN: 251488 Hom.: 0 AF XY: 0.0000883 AC XY: 12 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000363 AC: 53 AN: 1461888 Hom.: 0 Cov.: 31 AF XY: 0.0000303 AC XY: 22 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.000459

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 152084 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74288

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000494 Hom.: 0

Bravo AF: 0.0000227

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 05, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CLP1 protein function. ClinVar contains an entry for this variant (Variation ID: 1446127). This variant has not been reported in the literature in individuals affected with CLP1-related conditions. This variant is present in population databases (rs374658636, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 78 of the CLP1 protein (p.Arg78Cys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.20
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.067	T;T;T;.;T;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;.;D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.26	T;T;T;T;T;T
MetaSVM	Benign	-0.87	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-4.1	D;D;D;D;D;D
REVEL	Benign	0.15
Sift	Uncertain	0.0010	D;D;D;D;D;D
Sift4G	Uncertain	0.039	D;D;D;D;D;D
Polyphen		0.96, 0.99	.;.;D;.;D;D
Vest4		0.44, 0.46, 0.47, 0.49
MVP		0.41
MPC		1.0
ClinPred		0.52	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs374658636; hg19: chr11-57427180; COSMIC: COSV57054597;