19-44961994-C-T

Variant names:

• chr19-44961994-C-T
• rs368725337
• NM_001294.4:c.104C>T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001282176.2(CLPTM1):​c.-203C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,457,456 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: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: CLPTM1 NM_001282176.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.08

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05707565).
• BS2: High AC in GnomAdExome4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLPTM1	NM_001294.4	c.104C>T	p.Pro35Leu	missense_variant	Exon 2 of 14	ENST00000337392.10	NP_001285.1
CLPTM1	NM_001282176.2	c.-203C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 14		NP_001269105.1
CLPTM1	NM_001282175.2	c.62C>T	p.Pro21Leu	missense_variant	Exon 2 of 14		NP_001269104.1
CLPTM1	NM_001282176.2	c.-203C>T		5_prime_UTR_variant	Exon 2 of 14		NP_001269105.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLPTM1	ENST00000337392.10	c.104C>T	p.Pro35Leu	missense_variant	Exon 2 of 14	1	NM_001294.4	ENSP00000336994.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000122 AC: 3 AN: 245502 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 133212

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: 0.0000270

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1457456 Hom.: 0 Cov.: 30 AF XY: 0.0000124 AC XY: 9 AN XY: 725236

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.104C>T (p.P35L) alteration is located in exon 2 (coding exon 2) of the CLPTM1 gene. This alteration results from a C to T substitution at nucleotide position 104, causing the proline (P) at amino acid position 35 to be replaced by a leucine (L). 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	0.067
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	9.5
DANN	Benign	0.83
DEOGEN2	Benign	0.026	.;T;T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.085	N
LIST_S2	Benign	0.51	T;T;T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.057	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	.;N;.
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.1	N;N;.
REVEL	Benign	0.014
Sift	Benign	0.33	T;T;.
Sift4G	Benign	0.24	T;T;T
Polyphen		0.0020	.;B;.
Vest4		0.27
MVP		0.093
MPC		0.77
ClinPred		0.096	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.022
gMVP		0.48

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: rs368725337; hg19: chr19-45465251;