19-44955419-C-A

Variant names:

• chr19-44955419-C-A
• rs1390106775
• NM_001294.4:c.24C>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001294.4(CLPTM1):​c.24C>A​(p.Asp8Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000012 in 1,168,070 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: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: CLPTM1 NM_001294.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.82

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24954373).
• BS2: High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLPTM1	NM_001294.4	c.24C>A	p.Asp8Glu	missense_variant	Exon 1 of 14	ENST00000337392.10	NP_001285.1
CLPTM1	NM_001282175.2	c.30+334C>A		intron_variant	Intron 1 of 13		NP_001269104.1
CLPTM1	NM_001282176.2	c.-235+718C>A		intron_variant	Intron 1 of 13		NP_001269105.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLPTM1	ENST00000337392.10	c.24C>A	p.Asp8Glu	missense_variant	Exon 1 of 14	1	NM_001294.4	ENSP00000336994.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000120 AC: 14 AN: 1168070 Hom.: 0 Cov.: 30 AF XY: 0.0000142 AC XY: 8 AN XY: 562024

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000145

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.24C>A (p.D8E) alteration is located in exon 1 (coding exon 1) of the CLPTM1 gene. This alteration results from a C to A substitution at nucleotide position 24, causing the aspartic acid (D) at amino acid position 8 to be replaced by a glutamic acid (E). 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	0.071
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.024	T;T
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.50	T;T
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.18	N;.
REVEL	Benign	0.12
Sift	Benign	0.33	T;.
Sift4G	Benign	0.96	T;T
Polyphen		0.98	D;.
Vest4		0.22
MutPred		0.085		Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);
MVP		0.50
MPC		1.6
ClinPred		0.79	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.36

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: rs1390106775; hg19: chr19-45458676;