chr5-1320631-T-C

Variant names:

• chr5-1320631-T-C
• rs952234952
• NM_030782.5:c.1517A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_030782.5(CLPTM1L):​c.1517A>G​(p.Tyr506Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000101 in 1,389,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: CLPTM1L NM_030782.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.37
• Publications: 0 publications found

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

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.948

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030782.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLPTM1L	NM_030782.5	MANE Select	c.1517A>G	p.Tyr506Cys	missense	Exon 16 of 17	NP_110409.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLPTM1L	ENST00000320895.10	TSL:1 MANE Select	c.1517A>G	p.Tyr506Cys	missense	Exon 16 of 17	ENSP00000313854.5	Q96KA5-1
	CLPTM1L	ENST00000507807.3	TSL:1	c.1010A>G	p.Tyr337Cys	missense	Exon 13 of 14	ENSP00000423321.1	G5E9Z2
	CLPTM1L	ENST00000966757.1		c.1721A>G	p.Tyr574Cys	missense	Exon 17 of 18	ENSP00000636816.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000101 AC: 14 AN: 1389726 Hom.: 0 Cov.: 30 AF XY: 0.0000102 AC XY: 7 AN XY: 684436

African (AFR) AF: 0.0000319 AC: 1 AN: 31324

American (AMR) AF: 0.00 AC: 0 AN: 35162

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25020

East Asian (EAS) AF: 0.00 AC: 0 AN: 35324

South Asian (SAS) AF: 0.0000127 AC: 1 AN: 78528

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48776

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4268

European-Non Finnish (NFE) AF: 0.0000112 AC: 12 AN: 1073778

Other (OTH) AF: 0.00 AC: 0 AN: 57546

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.053	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		7.4
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-8.2	D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.80		Gain of catalytic residue at L507 (P = 0.0169)
MVP		0.68
MPC		1.2
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.89
Mutation Taster		=5/95	disease causing

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

Other links and lift over

dbSNP: rs952234952; hg19: chr5-1320746;