chr13-48707418-A-G

Position:

• chr13-48707418-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001308476.3(CYSLTR2):​c.601A>G​(p.Met201Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0225 in 1,614,114 control chromosomes in the GnomAD database, including 481 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (31 hom., cov: 32)
  • Exomes 𝑓: 0.023 (450 hom.)
• Consequence: CYSLTR2 NM_001308476.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.481

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004935324).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0167 (2539/152282) while in subpopulation NFE AF= 0.0269 (1827/67994). AF 95% confidence interval is 0.0258. There are 31 homozygotes in gnomad4. There are 1131 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 31 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYSLTR2	NM_001308476.3	c.601A>G	p.Met201Val	missense_variant	5/5	ENST00000682523.1	NP_001295405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYSLTR2	ENST00000682523.1	c.601A>G	p.Met201Val	missense_variant	5/5		NM_001308476.3	ENSP00000508181.1
CYSLTR2	ENST00000614739.4	c.601A>G	p.Met201Val	missense_variant	5/5	1		ENSP00000477930.1
CYSLTR2	ENST00000282018.4	c.601A>G	p.Met201Val	missense_variant	1/1	6		ENSP00000282018.3

Frequencies

GnomAD3 genomes AF: 0.0167 AC: 2540 AN: 152164 Hom.: 31 Cov.: 32

Gnomad AFR AF: 0.00473

Gnomad AMI AF: 0.0658

Gnomad AMR AF: 0.0134

Gnomad ASJ AF: 0.0309

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0108

Gnomad FIN AF: 0.00320

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0269

Gnomad OTH AF: 0.0244

GnomAD3 exomes AF: 0.0170 AC: 4259 AN: 251034 Hom.: 56 AF XY: 0.0176 AC XY: 2381 AN XY: 135664

Gnomad AFR exome AF: 0.00486

Gnomad AMR exome AF: 0.00995

Gnomad ASJ exome AF: 0.0337

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00957

Gnomad FIN exome AF: 0.00352

Gnomad NFE exome AF: 0.0265

Gnomad OTH exome AF: 0.0209

GnomAD4 exome AF: 0.0231 AC: 33761 AN: 1461832 Hom.: 450 Cov.: 31 AF XY: 0.0230 AC XY: 16709 AN XY: 727218

Gnomad4 AFR exome AF: 0.00367

Gnomad4 AMR exome AF: 0.0109

Gnomad4 ASJ exome AF: 0.0305

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0100

Gnomad4 FIN exome AF: 0.00470

Gnomad4 NFE exome AF: 0.0269

Gnomad4 OTH exome AF: 0.0192

GnomAD4 genome AF: 0.0167 AC: 2539 AN: 152282 Hom.: 31 Cov.: 32 AF XY: 0.0152 AC XY: 1131 AN XY: 74478

Gnomad4 AFR AF: 0.00472

Gnomad4 AMR AF: 0.0134

Gnomad4 ASJ AF: 0.0309

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0108

Gnomad4 FIN AF: 0.00320

Gnomad4 NFE AF: 0.0269

Gnomad4 OTH AF: 0.0242

Alfa AF: 0.0253 Hom.: 80

Bravo AF: 0.0161

TwinsUK AF: 0.0251 AC: 93

ALSPAC AF: 0.0259 AC: 100

ESP6500AA AF: 0.00477 AC: 21

ESP6500EA AF: 0.0252 AC: 217

ExAC AF: 0.0170 AC: 2064

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.0280

EpiControl AF: 0.0301

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Oct 04, 2015

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	12
DANN	Benign	0.51
DEOGEN2	Benign	0.045	T;T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.49	.;T
MetaRNN	Benign	0.0049	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;L
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.2	.;N
REVEL	Benign	0.058
Sift	Uncertain	0.010	.;D
Sift4G	Benign	0.29	T;T
Polyphen		0.078	B;B
Vest4		0.073
MPC		0.24
ClinPred		0.0044	T
GERP RS		0.55
Varity_R		0.18
gMVP		0.14

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: rs41347648; hg19: chr13-49281554;