Genetic Variant CLPTM1:p.Ala2Val (chr19-44955400-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4_ModerateBS2

The NM_001294.4(CLPTM1):c.5C>T(p.Ala2Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000478 in 1,318,350 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 (★). Synonymous variant affecting the same amino acid position (i.e. A2A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

CLPTM1
NM_001294.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.82

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 -4 ACMG points.

PM1

In a modified_residue N-acetylalanine (size 0) in uniprot entity CLPT1_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=0.20927477).

BS2

High AC in GnomAd4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLPTM1	NM_001294.4 link	c.5C>T	p.Ala2Val	missense_variant	Exon 1 of 14	ENST00000337392.10	NP_001285.1	O96005-1A0A0S2Z3H2
CLPTM1	NM_001282175.2 link	c.30+315C>T		intron_variant	Intron 1 of 13		NP_001269104.1	O96005-4
CLPTM1	NM_001282176.2 link	c.-235+699C>T		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.5C>T	p.Ala2Val	missense_variant	Exon 1 of 14	1	NM_001294.4	ENSP00000336994.4		O96005-1

Frequencies

GnomAD3 genomes

AF:

0.000132

AC:

AN:

151814

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.000865

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

GnomAD3 exomes

AF:

0.000333

AC:

AN:

12024

Hom.:

AF XY:

0.000154

AC XY:

AN XY:

6492

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.000618

Gnomad OTH exome

AF:

0.00287

GnomAD4 exome

AF:

0.0000369

AC:

AN:

1166536

Hom.:

Cov.:

AF XY:

0.0000392

AC XY:

AN XY:

561740

show subpopulations

Gnomad4 AFR exome

AF:

0.0000433

Gnomad4 AMR exome

AF:

0.000668

Gnomad4 ASJ exome

AF:

0.000637

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.000252

GnomAD4 genome

AF:

0.000132

AC:

AN:

151814

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74132

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.000865

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

Bravo

AF:

0.000287

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5C>T (p.A2V) alteration is located in exon 1 (coding exon 1) of the CLPTM1 gene. This alteration results from a C to T substitution at nucleotide position 5, causing the alanine (A) at amino acid position 2 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

0.46

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Benign

-0.090

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.026

T;T

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.67

T;T

M_CAP

Pathogenic

0.46

MetaRNN

Benign

0.21

T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

0.55

N;.

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

0.020

N;.

REVEL

Benign

0.073

Sift

Benign

0.28

T;.

Sift4G

Uncertain

0.060

T;T

Polyphen

1.0

D;.

Vest4

0.45

MutPred

0.31

Gain of stability (P = 0.0174);Gain of stability (P = 0.0174);

MVP

0.38

MPC

1.5

ClinPred

0.32

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.15

gMVP

0.67

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

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