Genetic Variant CLPTM1:p.Gly32Arg (chr19-44961984-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001294.4(CLPTM1):c.94G>A(p.Gly32Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000796 in 1,607,406 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 0.00040 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000046 ( 0 hom. )

Consequence

CLPTM1
NM_001294.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.94

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 Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.028418422).

BS2

High AC in GnomAd4 at 61 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLPTM1	NM_001294.4 link	c.94G>A	p.Gly32Arg	missense_variant	Exon 2 of 14	ENST00000337392.10	NP_001285.1	O96005-1A0A0S2Z3H2
CLPTM1	NM_001282175.2 link	c.52G>A	p.Gly18Arg	missense_variant	Exon 2 of 14		NP_001269104.1	O96005-4
CLPTM1	NM_001282176.2 link	c.-213G>A		5_prime_UTR_variant	Exon 2 of 14		NP_001269105.1	O96005-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLPTM1	ENST00000337392.10 link	c.94G>A	p.Gly32Arg	missense_variant	Exon 2 of 14	1	NM_001294.4	ENSP00000336994.4		O96005-1

Frequencies

GnomAD3 genomes

AF:

0.000401

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00142

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

GnomAD3 exomes

AF:

0.000115

AC:

AN:

242844

Hom.:

AF XY:

0.0000682

AC XY:

AN XY:

131884

show subpopulations

Gnomad AFR exome

AF:

0.00145

Gnomad AMR exome

AF:

0.0000611

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:

0.0000273

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000460

AC:

AN:

1455148

Hom.:

Cov.:

AF XY:

0.0000373

AC XY:

AN XY:

724152

show subpopulations

Gnomad4 AFR exome

AF:

0.00160

Gnomad4 AMR exome

AF:

0.0000698

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:

0.00000631

Gnomad4 OTH exome

AF:

0.0000667

GnomAD4 genome

AF:

0.000401

AC:

AN:

152258

Hom.:

Cov.:

AF XY:

0.000390

AC XY:

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.00142

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

Alfa

AF:

0.000126

Hom.:

Bravo

AF:

0.000540

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000140

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000595

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.94G>A (p.G32R) alteration is located in exon 2 (coding exon 2) of the CLPTM1 gene. This alteration results from a G to A substitution at nucleotide position 94, causing the glycine (G) at amino acid position 32 to be replaced by an arginine (R). 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

Benign

0.24

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.051

.;T;T

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.87

D;D;D

M_CAP

Benign

0.0076

MetaRNN

Benign

0.028

T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.81

.;L;.

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-2.1

N;N;.

REVEL

Uncertain

0.29

Sift

Benign

0.044

D;D;.

Sift4G

Uncertain

0.039

D;T;D

Polyphen

1.0

.;D;.

Vest4

0.48

MutPred

0.19

.;Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);

MVP

0.37

MPC

1.1

ClinPred

0.062

GERP RS

5.3

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Varity_R

0.053

gMVP

0.65

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