5-1318437-T-C

Position:

• chr5-1318437-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_030782.5(CLPTM1L):​c.1549A>G​(p.Lys517Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CLPTM1L NM_030782.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.78

Genes affected

CLPTM1L (HGNC:24308): (CLPTM1 like) The protein encoded by this gene is a membrane protein whose overexpression in cisplatin-sensitive cells causes apoptosis. Polymorphisms in this gene have been reported to increase susceptibility to several cancers, including lung, pancreatic, and breast cancers. [provided by RefSeq, Nov 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLPTM1L	NM_030782.5	c.1549A>G	p.Lys517Glu	missense_variant	17/17	ENST00000320895.10	NP_110409.2
CLPTM1L	XM_011514144.3	c.1546A>G	p.Lys516Glu	missense_variant	17/17		XP_011512446.1
CLPTM1L	XM_024446222.2	c.1015A>G	p.Lys339Glu	missense_variant	15/15		XP_024301990.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLPTM1L	ENST00000320895.10	c.1549A>G	p.Lys517Glu	missense_variant	17/17	1	NM_030782.5	ENSP00000313854.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250558 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135590

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: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 24, 2024

The c.1549A>G (p.K517E) alteration is located in exon 17 (coding exon 17) of the CLPTM1L gene. This alteration results from a A to G substitution at nucleotide position 1549, causing the lysine (K) at amino acid position 517 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	0.32
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T;.;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D;.;D
M_CAP	Benign	0.074	D
MetaRNN	Uncertain	0.49	T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Uncertain	2.6	M;.;.
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.0	D;D;.
REVEL	Benign	0.19
Sift	Uncertain	0.0040	D;D;.
Sift4G	Uncertain	0.024	D;D;D
Polyphen		0.99	D;B;B
Vest4		0.38
MutPred		0.55		Loss of methylation at K517 (P = 0.0012);.;.;
MVP		0.71
MPC		0.96
ClinPred		0.99	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.52
gMVP		0.78

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: rs755487218; hg19: chr5-1318552;