17-4499168-G-A

Variant names:

• chr17-4499168-G-A
• rs1453027012
• NM_001124758.3:c.121G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001124758.3(SPNS2):​c.121G>A​(p.Gly41Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000245 in 1,224,994 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.0000067 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000019 (0 hom.)
• Consequence: SPNS2 NM_001124758.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.05

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-AS1 (HGNC:55787): (SPNS2 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2314848).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPNS2	NM_001124758.3	c.121G>A	p.Gly41Arg	missense_variant	Exon 1 of 13	ENST00000329078.8	NP_001118230.1
SPNS2	XR_007065260.1	n.288G>A		non_coding_transcript_exon_variant	Exon 1 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPNS2	ENST00000329078.8	c.121G>A	p.Gly41Arg	missense_variant	Exon 1 of 13	1	NM_001124758.3	ENSP00000333292.3
SPNS2-AS1	ENST00000416958.1	n.48+459C>T		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes AF: 0.00000667 AC: 1 AN: 149884 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.000101

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000186 AC: 2 AN: 1075110 Hom.: 0 Cov.: 30 AF XY: 0.00000195 AC XY: 1 AN XY: 512542

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: 0.00000218

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000667 AC: 1 AN: 149884 Hom.: 0 Cov.: 32 AF XY: 0.0000137 AC XY: 1 AN XY: 73100

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000101

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.027	T
Eigen	Benign	-0.024
Eigen_PC	Benign	-0.027
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.56	T
M_CAP	Pathogenic	0.46	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.96	N
REVEL	Benign	0.12
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.015	D
Polyphen		1.0	D
Vest4		0.20
MutPred		0.34		Gain of methylation at G41 (P = 0.0056);
MVP		0.23
MPC		0.95
ClinPred		0.41	T
GERP RS		3.1
Varity_R		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: rs1453027012; hg19: chr17-4402463;