17-4499252-A-C

Variant names:

• chr17-4499252-A-C
• NM_001124758.3:c.205A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001124758.3(SPNS2):​c.205A>C​(p.Thr69Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 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)
• Consequence: SPNS2 NM_001124758.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.74
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03662759).

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.205A>C	p.Thr69Pro	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.205A>C	p.Thr69Pro	missense	Exon 1 of 13	ENSP00000333292.3	Q8IVW8
	SPNS2	ENST00000947403.1		c.205A>C	p.Thr69Pro	missense	Exon 1 of 13	ENSP00000617462.1
	SPNS2	ENST00000932033.1		c.205A>C	p.Thr69Pro	missense	Exon 1 of 12	ENSP00000602092.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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	0.052
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	9.7
DANN	Benign	0.77
DEOGEN2	Benign	0.023	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.19	T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.037	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.7
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.51	N
REVEL	Benign	0.034
Sift	Benign	0.27	T
Sift4G	Benign	0.080	T
Polyphen		0.0	B
Vest4		0.082
MutPred		0.18		Loss of phosphorylation at T69 (P = 0.0017)
MVP		0.048
MPC		1.0
ClinPred		0.049	T
GERP RS		-2.1
PromoterAI		-0.032	Neutral
Varity_R		0.091

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

hg19: chr17-4402547;