17-4499343-G-A

Position:

• chr17-4499343-G-A

Variant summary

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

The NM_001124758.3(SPNS2):​c.296G>A​(p.Arg99His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SPNS2 NM_001124758.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.99

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]

SPNS2 (HGNC:):

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/exons	MANE	Protein	UniProt
SPNS2	NM_001124758.3	c.296G>A	p.Arg99His	missense_variant	1/13	ENST00000329078.8	NP_001118230.1
SPNS2	XR_007065260.1	n.463G>A		non_coding_transcript_exon_variant	1/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPNS2	ENST00000329078.8	c.296G>A	p.Arg99His	missense_variant	1/13	1	NM_001124758.3	ENSP00000333292.3
SPNS2-AS1	ENST00000416958.1	n.48+284C>T		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1304800 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 642780

Gnomad4 AFR exome AF: 0.00

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: 0.00

GnomAD4 genome Cov.: 32

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

Aug 07, 2024

The c.296G>A (p.R99H) alteration is located in exon 1 (coding exon 1) of the SPNS2 gene. This alteration results from a G to A substitution at nucleotide position 296, causing the arginine (R) at amino acid position 99 to be replaced by a histidine (H). 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	0.18
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.065	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.93	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.0	N
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.13
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.021	D
Polyphen		1.0	D
Vest4		0.25
MutPred		0.40		Loss of methylation at R99 (P = 0.0112);
MVP		0.60
MPC		1.9
ClinPred		0.77	D
GERP RS		3.0
Varity_R		0.19

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: rs1395107719; hg19: chr17-4402638;