rs3745733

Variant names:

• chr19-48629377-G-A
• rs3745733
• NM_020126.5:c.1569G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-48629377-G-A
• chr19-48629377-G-C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_020126.5(SPHK2):​c.1569G>A​(p.Leu523Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 1,611,726 control chromosomes in the GnomAD database, including 14,115 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.11 (1145 hom., cov: 33)
  • Exomes 𝑓: 0.13 (12970 hom.)
• Consequence: SPHK2 NM_020126.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0850
• Publications: 14 publications found

Genes affected

SPHK2 (HGNC:18859): (sphingosine kinase 2) This gene encodes one of two sphingosine kinase isozymes that catalyze the phosphorylation of sphingosine into sphingosine 1-phosphate. Sphingosine 1-phosphate mediates many cellular processes including migration, proliferation and apoptosis, and also plays a role in several types of cancer by promoting angiogenesis and tumorigenesis. The encoded protein may play a role in breast cancer proliferation and chemoresistance. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Aug 2011]

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP7: Synonymous conserved (PhyloP=0.085 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.142 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020126.5. 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
	SPHK2	NM_020126.5	MANE Select	c.1569G>A	p.Leu523Leu	synonymous	Exon 7 of 7	NP_064511.2
	SPHK2	NM_001204159.3		c.1569G>A	p.Leu523Leu	synonymous	Exon 7 of 7	NP_001191088.1	Q9NRA0-1
	SPHK2	NM_001204160.3		c.1461G>A	p.Leu487Leu	synonymous	Exon 6 of 6	NP_001191089.1	Q9NRA0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPHK2	ENST00000245222.9	TSL:1 MANE Select	c.1569G>A	p.Leu523Leu	synonymous	Exon 7 of 7	ENSP00000245222.3	Q9NRA0-1
	SPHK2	ENST00000599029.2	TSL:1	c.1461G>A	p.Leu487Leu	synonymous	Exon 5 of 6	ENSP00000472983.1	M0R344
	SPHK2	ENST00000598088.5	TSL:1	c.1569G>A	p.Leu523Leu	synonymous	Exon 7 of 7	ENSP00000469158.1	Q9NRA0-1

Frequencies

GnomAD3 genomes AF: 0.110 AC: 16758 AN: 152172 Hom.: 1146 Cov.: 33

Gnomad AFR AF: 0.0400

Gnomad AMI AF: 0.180

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.140

Gnomad EAS AF: 0.0724

Gnomad SAS AF: 0.109

Gnomad FIN AF: 0.175

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.144

Gnomad OTH AF: 0.0984

GnomAD2 exomes AF: 0.123 AC: 30063 AN: 245088 AF XY: 0.126

Gnomad AFR exome AF: 0.0367

Gnomad AMR exome AF: 0.0891

Gnomad ASJ exome AF: 0.145

Gnomad EAS exome AF: 0.0734

Gnomad FIN exome AF: 0.169

Gnomad NFE exome AF: 0.147

Gnomad OTH exome AF: 0.125

GnomAD4 exome AF: 0.130 AC: 189873 AN: 1459436 Hom.: 12970 Cov.: 33 AF XY: 0.130 AC XY: 94526 AN XY: 725996

African (AFR) AF: 0.0404 AC: 1352 AN: 33468

American (AMR) AF: 0.0936 AC: 4181 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.145 AC: 3772 AN: 26082

East Asian (EAS) AF: 0.0672 AC: 2665 AN: 39654

South Asian (SAS) AF: 0.106 AC: 9179 AN: 86196

European-Finnish (FIN) AF: 0.170 AC: 8811 AN: 51924

Middle Eastern (MID) AF: 0.111 AC: 639 AN: 5756

European-Non Finnish (NFE) AF: 0.137 AC: 152426 AN: 1111386

Other (OTH) AF: 0.114 AC: 6848 AN: 60320

GnomAD4 genome AF: 0.110 AC: 16772 AN: 152290 Hom.: 1145 Cov.: 33 AF XY: 0.112 AC XY: 8337 AN XY: 74462

African (AFR) AF: 0.0399 AC: 1660 AN: 41570

American (AMR) AF: 0.109 AC: 1675 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 486 AN: 3468

East Asian (EAS) AF: 0.0726 AC: 376 AN: 5178

South Asian (SAS) AF: 0.111 AC: 535 AN: 4832

European-Finnish (FIN) AF: 0.175 AC: 1857 AN: 10622

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.144 AC: 9787 AN: 67994

Other (OTH) AF: 0.0969 AC: 205 AN: 2116

Alfa AF: 0.128 Hom.: 844

Bravo AF: 0.0988

Asia WGS AF: 0.0680 AC: 238 AN: 3478

EpiCase AF: 0.133

EpiControl AF: 0.134

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	2.4
DANN	Benign	0.90
PhyloP100		0.085
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3745733; hg19: chr19-49132634; COSMIC: COSV55337487; COSMIC: COSV55337487;