Genetic Variant CLPTM1:p.Gly18Glu (chr19-44955448-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001294.4(CLPTM1):c.53G>A(p.Gly18Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000524 in 1,334,716 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 (no stars).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000050 ( 0 hom. )

Consequence

CLPTM1
NM_001294.4 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 2.15

Variant links:

Genes affected

CLPTM1 (HGNC:2087): (CLPTM1 regulator of GABA type A receptor forward trafficking) Predicted to be involved in regulation of T cell differentiation in thymus. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

CLPTM1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15918973).

BS2

High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLPTM1	NM_001294.4 link	c.53G>A	p.Gly18Glu	missense_variant	Exon 1 of 14	ENST00000337392.10	NP_001285.1	O96005-1A0A0S2Z3H2
CLPTM1	NM_001282175.2 link	c.30+363G>A		intron_variant	Intron 1 of 13		NP_001269104.1	O96005-4
CLPTM1	NM_001282176.2 link	c.-235+747G>A		intron_variant	Intron 1 of 13		NP_001269105.1	O96005-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLPTM1	ENST00000337392.10 link	c.53G>A	p.Gly18Glu	missense_variant	Exon 1 of 14	1	NM_001294.4	ENSP00000336994.4		O96005-1

Frequencies

GnomAD3 genomes

AF:

0.0000722

AC:

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000162

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000499

AC:

AN:

1182466

Hom.:

Cov.:

AF XY:

0.0000388

AC XY:

AN XY:

567544

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000356

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000542

Gnomad4 OTH exome

AF:

0.000103

GnomAD4 genome

AF:

0.0000722

AC:

AN:

152250

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000491

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

CLPTM1-related disorder

Uncertain:1

Mar 14, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CLPTM1 c.53G>A variant is predicted to result in the amino acid substitution p.Gly18Glu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.010% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.029

BayesDel_noAF

Benign

-0.28

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.023

T;T

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.16

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.59

T;T

M_CAP

Pathogenic

0.43

MetaRNN

Benign

0.16

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;.

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

0.17

N;.

REVEL

Benign

0.061

Sift

Benign

0.11

T;.

Sift4G

Uncertain

0.033

D;D

Polyphen

0.52

P;.

Vest4

0.31

MutPred

0.22

Gain of solvent accessibility (P = 0.0456);Gain of solvent accessibility (P = 0.0456);

MVP

0.26

MPC

0.98

ClinPred

0.43

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.11

gMVP

0.33

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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