17-4499262-C-T

Variant names:

• chr17-4499262-C-T
• rs1904384963
• NM_001124758.3:c.215C>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.215C>T​(p.Pro72Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000227 in 1,323,202 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P72R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: SPNS2 NM_001124758.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.54
• 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=0.16733092).

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.215C>T	p.Pro72Leu	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.215C>T	p.Pro72Leu	missense	Exon 1 of 13	ENSP00000333292.3	Q8IVW8
	SPNS2	ENST00000947403.1		c.215C>T	p.Pro72Leu	missense	Exon 1 of 13	ENSP00000617462.1
	SPNS2	ENST00000932033.1		c.215C>T	p.Pro72Leu	missense	Exon 1 of 12	ENSP00000602092.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000227 AC: 3 AN: 1323202 Hom.: 0 Cov.: 32 AF XY: 0.00000153 AC XY: 1 AN XY: 652122

African (AFR) AF: 0.00 AC: 0 AN: 26644

American (AMR) AF: 0.00 AC: 0 AN: 28116

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23094

East Asian (EAS) AF: 0.0000342 AC: 1 AN: 29242

South Asian (SAS) AF: 0.00 AC: 0 AN: 72972

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32722

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4040

European-Non Finnish (NFE) AF: 0.00000190 AC: 2 AN: 1051364

Other (OTH) AF: 0.00 AC: 0 AN: 55008

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.036	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.43
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.57	T
M_CAP	Pathogenic	0.52	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.5
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.73	N
REVEL	Benign	0.025
Sift	Benign	0.25	T
Sift4G	Uncertain	0.0080	D
Polyphen		0.036	B
Vest4		0.20
MutPred		0.27		Loss of glycosylation at P72 (P = 0.012)
MVP		0.12
MPC		0.85
ClinPred		0.43	T
GERP RS		3.4
PromoterAI		0.016	Neutral
Varity_R		0.063
Mutation Taster		=79/21	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: rs1904384963; hg19: chr17-4402557;