17-4533107-CC-T

Variant names:

• chr17-4533107-CC-T
• rs1555537637
• NM_001124758.3:c.1066_1067delCCinsT

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001124758.3(SPNS2):​c.1066_1067delCCinsT​(p.Pro356CysfsTer35) 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
• 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 Gene-Disease associations (from GenCC):

• hearing loss, autosomal recessive 115

  Inheritance: Unknown, AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia

ACMG classification

Our verdict: Pathogenic. The variant received 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 VariationId is 521864.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPNS2	NM_001124758.3	MANE Select	c.1066_1067delCCinsT	p.Pro356CysfsTer35	frameshift missense	Exon 7 of 13	NP_001118230.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPNS2	ENST00000329078.8	TSL:1 MANE Select	c.1066_1067delCCinsT	p.Pro356CysfsTer35	frameshift missense	Exon 7 of 13	ENSP00000333292.3
	SPNS2	ENST00000571386.1	TSL:5	c.76_77delCCinsT	p.Pro26CysfsTer35	frameshift missense	Exon 1 of 6	ENSP00000461410.1
	SPNS2	ENST00000576635.6	TSL:3	n.-136_-135delCCinsT		upstream_gene	N/A

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

Jun 23, 2017

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Lines of evidence used in support of classification: CANDIDATE: Alteration(s) of Potential Clinical Relevance Detected

Jan 04, 2018

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Lines of evidence used in support of classification: CANDIDATE: Alteration(s) of Potential Clinical Relevance Detected

Hearing loss, autosomal recessive 115 Pathogenic:1

Jun 03, 2019

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.8
Mutation Taster		=18/182	disease causing (fs/PTC)

Splicing

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

Other links and lift over

dbSNP: rs1555537637; hg19: chr17-4436402;