13-48707418-A-G

Variant names:

• chr13-48707418-A-G
• rs41347648
• NM_001308476.3:c.601A>G

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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
• Publications: 27 publications found

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

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 31 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001308476.3. 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
	CYSLTR2	NM_001308476.3	MANE Select	c.601A>G	p.Met201Val	missense	Exon 5 of 5	NP_001295405.1	Q9NS75
	CYSLTR2	NM_001308465.3		c.601A>G	p.Met201Val	missense	Exon 6 of 6	NP_001295394.1	Q9NS75
	CYSLTR2	NM_001308467.3		c.601A>G	p.Met201Val	missense	Exon 6 of 6	NP_001295396.1	Q9NS75

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYSLTR2	ENST00000682523.1	MANE Select	c.601A>G	p.Met201Val	missense	Exon 5 of 5	ENSP00000508181.1	Q9NS75
	CYSLTR2	ENST00000614739.4	TSL:1	c.601A>G	p.Met201Val	missense	Exon 5 of 5	ENSP00000477930.1	Q9NS75
	CYSLTR2	ENST00000282018.4	TSL:6	c.601A>G	p.Met201Val	missense	Exon 1 of 1	ENSP00000282018.3	Q9NS75

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

GnomAD2 exomes AF: 0.0170 AC: 4259 AN: 251034 AF XY: 0.0176

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 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

African (AFR) AF: 0.00367 AC: 123 AN: 33480

American (AMR) AF: 0.0109 AC: 489 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0305 AC: 798 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0100 AC: 863 AN: 86258

European-Finnish (FIN) AF: 0.00470 AC: 251 AN: 53366

Middle Eastern (MID) AF: 0.0203 AC: 117 AN: 5768

European-Non Finnish (NFE) AF: 0.0269 AC: 29961 AN: 1112008

Other (OTH) AF: 0.0192 AC: 1157 AN: 60392

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

African (AFR) AF: 0.00472 AC: 196 AN: 41564

American (AMR) AF: 0.0134 AC: 205 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0309 AC: 107 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.0108 AC: 52 AN: 4828

European-Finnish (FIN) AF: 0.00320 AC: 34 AN: 10620

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0269 AC: 1827 AN: 67994

Other (OTH) AF: 0.0242 AC: 51 AN: 2110

Alfa AF: 0.0241 Hom.: 162

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

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.48
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.058
Sift	Uncertain	0.010	D
Sift4G	Benign	0.29	T
Polyphen		0.078	B
Vest4		0.073
MPC		0.24
ClinPred		0.0044	T
GERP RS		0.55
Varity_R		0.18
gMVP		0.14
Mutation Taster		=95/5	polymorphism (auto)

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: rs41347648; hg19: chr13-49281554;