17-4499199-C-T

Variant names:

• chr17-4499199-C-T
• rs1904375420
• NM_001124758.3:c.152C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001124758.3(SPNS2):​c.152C>T​(p.Ser51Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000163 in 1,226,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: SPNS2 NM_001124758.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.05
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07111898).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001124758.3. 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
	SPNS2	NM_001124758.3	MANE Select	c.152C>T	p.Ser51Leu	missense	Exon 1 of 13	NP_001118230.1	Q8IVW8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPNS2	ENST00000329078.8	TSL:1 MANE Select	c.152C>T	p.Ser51Leu	missense	Exon 1 of 13	ENSP00000333292.3	Q8IVW8
	SPNS2	ENST00000947403.1		c.152C>T	p.Ser51Leu	missense	Exon 1 of 13	ENSP00000617462.1
	SPNS2	ENST00000932033.1		c.152C>T	p.Ser51Leu	missense	Exon 1 of 12	ENSP00000602092.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000163 AC: 2 AN: 1226554 Hom.: 0 Cov.: 31 AF XY: 0.00000166 AC XY: 1 AN XY: 601080

African (AFR) AF: 0.00 AC: 0 AN: 24664

American (AMR) AF: 0.00 AC: 0 AN: 15882

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19084

East Asian (EAS) AF: 0.00 AC: 0 AN: 26716

South Asian (SAS) AF: 0.00 AC: 0 AN: 58634

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29966

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3452

European-Non Finnish (NFE) AF: 0.00000200 AC: 2 AN: 998488

Other (OTH) AF: 0.00 AC: 0 AN: 49668

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	22
DANN	Uncertain	0.97
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.60	T
M_CAP	Uncertain	0.099	D
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.0
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.041
Sift	Benign	0.27	T
Sift4G	Benign	0.19	T
Polyphen		0.0010	B
Vest4		0.064
MutPred		0.40		Gain of sheet (P = 0.0085)
MVP		0.12
MPC		0.71
ClinPred		0.25	T
GERP RS		0.57
PromoterAI		-0.034	Neutral
Varity_R		0.058
Mutation Taster		=90/10	polymorphism

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: rs1904375420; hg19: chr17-4402494;