17-4533106-CCC-CT

Position:

• chr17-4533106-CCC-CT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001124758.3(SPNS2):​c.1066_1067delCCinsT​(p.Pro356fs) variant causes a frameshift, missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SPNS2 NM_001124758.3 frameshift, missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 1.83

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-4533107-CC-T is Pathogenic according to our data. Variant chr17-4533107-CC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 521864.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPNS2	NM_001124758.3	c.1066_1067delCCinsT	p.Pro356fs	frameshift_variant, missense_variant	7/13	ENST00000329078.8	NP_001118230.1
SPNS2	XM_047435339.1	c.613_614delCCinsT	p.Pro205fs	frameshift_variant, missense_variant	7/13		XP_047291295.1
SPNS2	XR_007065260.1	n.1233_1234delCCinsT		non_coding_transcript_exon_variant	7/13
SPNS2	XR_007065261.1	n.903_904delCCinsT		non_coding_transcript_exon_variant	5/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPNS2	ENST00000329078.8	c.1066_1067delCCinsT	p.Pro356fs	frameshift_variant, missense_variant	7/13	1	NM_001124758.3	ENSP00000333292.3
SPNS2	ENST00000571386.1	c.76_77delCCinsT	p.Pro26fs	frameshift_variant, missense_variant	1/6	5		ENSP00000461410.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 23, 2017	Lines of evidence used in support of classification: CANDIDATE: Alteration(s) of Potential Clinical Relevance Detected -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 04, 2018	Lines of evidence used in support of classification: CANDIDATE: Alteration(s) of Potential Clinical Relevance Detected -

Hearing loss, autosomal recessive 115 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 03, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555537637; hg19: chr17-4436402;