13-48707334-C-T

Variant names:

• chr13-48707334-C-T
• rs1954525282
• NM_001308476.3:c.517C>T

Variant summary

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

The NM_001308476.3(CYSLTR2):​c.517C>T​(p.Leu173Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,796 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: CYSLTR2 NM_001308476.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.60

Genes affected

CYSLTR2 (HGNC:18274): (cysteinyl leukotriene receptor 2) The cysteinyl leukotrienes LTC4, LTD4, and LTE4 are important mediators of human bronchial asthma. Pharmacologic studies have determined that cysteinyl leukotrienes activate at least 2 receptors, the protein encoded by this gene and CYSLTR1. This encoded receptor is a member of the superfamily of G protein-coupled receptors. It seems to play a major role in endocrine and cardiovascular systems. [provided by RefSeq, Jul 2008]

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 rank	MANE	Protein	UniProt
CYSLTR2	NM_001308476.3	c.517C>T	p.Leu173Phe	missense_variant	Exon 5 of 5	ENST00000682523.1	NP_001295405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYSLTR2	ENST00000682523.1	c.517C>T	p.Leu173Phe	missense_variant	Exon 5 of 5		NM_001308476.3	ENSP00000508181.1
CYSLTR2	ENST00000614739.4	c.517C>T	p.Leu173Phe	missense_variant	Exon 5 of 5	1		ENSP00000477930.1
CYSLTR2	ENST00000282018.4	c.517C>T	p.Leu173Phe	missense_variant	Exon 1 of 1	6		ENSP00000282018.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461796 Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11 AN XY: 727202

Gnomad4 AFR exome AF: 0.000329

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: 0.00

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.517C>T (p.L173F) alteration is located in exon 1 (coding exon 1) of the CYSLTR2 gene. This alteration results from a C to T substitution at nucleotide position 517, causing the leucine (L) at amino acid position 173 to be replaced by a phenylalanine (F). 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	0.25
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.024	T;T
Eigen	Benign	0.034
Eigen_PC	Benign	0.020
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.58	.;T
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.53	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;L
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	0.030	.;N
REVEL	Benign	0.14
Sift	Benign	0.46	.;T
Sift4G	Benign	0.40	T;T
Polyphen		0.88	P;P
Vest4		0.60
MutPred		0.56		Gain of catalytic residue at A168 (P = 0);Gain of catalytic residue at A168 (P = 0);
MVP		0.69
MPC		0.60
ClinPred		0.69	D
GERP RS		5.7
Varity_R		0.19
gMVP		0.084

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: rs1954525282; hg19: chr13-49281470;