17-4525151-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001124758.3(SPNS2):c.531C>G(p.Phe177Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,240 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 32)
• Consequence: SPNS2 NM_001124758.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.69

Genes affected

SPNS2 (HGNC:26992): (SPNS lysolipid transporter 2, sphingosine-1-phosphate) The protein encoded by this gene is a transporter of sphingosine 1-phosphate, a secreted lipid that is important in cardiovascular, immunological, and neural development. Defects in this gene are a cause of early onset progressive hearing loss. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3717625).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPNS2	NM_001124758.3	c.531C>G	p.Phe177Leu	missense_variant	3/13	ENST00000329078.8
SPNS2	XM_047435339.1	c.78C>G	p.Phe26Leu	missense_variant	3/13
SPNS2	XR_007065260.1	n.698C>G		non_coding_transcript_exon_variant	3/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPNS2	ENST00000329078.8	c.531C>G	p.Phe177Leu	missense_variant	3/13	1	NM_001124758.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152240 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74380

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 22, 2022

The c.531C>G (p.F177L) alteration is located in exon 3 (coding exon 3) of the SPNS2 gene. This alteration results from a C to G substitution at nucleotide position 531, causing the phenylalanine (F) at amino acid position 177 to be replaced by a leucine (L). 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	Uncertain	0.52
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
Cadd	Uncertain	25
Dann	Benign	0.97
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.023
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.48	N
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.21
Sift	Benign	0.92	T
Sift4G	Benign	1.0	T
Polyphen		0.015	B
Vest4		0.51
MutPred		0.53		Loss of catalytic residue at F177 (P = 0.1395);
MVP		0.45
MPC		2.0
ClinPred		0.76	D
GERP RS		5.2
Varity_R		0.34

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

Publications

LitVar

Other links and lift over

dbSNP: rs1023890716; hg19: chr17-4428446;