Genetic Variant SPNS2:p.Thr77_Gly79del (chr17-4499258-CCCCCCGGCA-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM4BS2

The NM_001124758.3(SPNS2):c.229_237delACCCCCGGC(p.Thr77_Gly79del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.000662 in 1,461,400 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.00069 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00066 ( 2 hom. )

Consequence

SPNS2
NM_001124758.3 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 3.65

Variant links:

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 links:

SPNS2-AS1 (HGNC:55787): (SPNS2 antisense RNA 1)

SPNS2-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_001124758.3.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPNS2	NM_001124758.3 link	c.229_237delACCCCCGGC	p.Thr77_Gly79del	conservative_inframe_deletion	Exon 1 of 13	ENST00000329078.8	NP_001118230.1	Q8IVW8
SPNS2	XR_007065260.1 link	n.396_404delACCCCCGGC		non_coding_transcript_exon_variant	Exon 1 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPNS2	ENST00000329078.8 link	c.229_237delACCCCCGGC	p.Thr77_Gly79del	conservative_inframe_deletion	Exon 1 of 13	1	NM_001124758.3	ENSP00000333292.3		Q8IVW8
SPNS2-AS1	ENST00000416958.1 link	n.48+360_48+368delTGCCGGGGG		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes

AF:

0.000693

AC:

105

AN:

151438

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00126

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000263

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000605

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000629

AC:

AN:

73108

AF XY:

0.000570

show subpopulations

Gnomad AFR exome

AF:

0.00218

Gnomad AMR exome

AF:

0.000342

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000368

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00101

Gnomad OTH exome

AF:

0.000903

GnomAD4 exome

AF:

0.000658

AC:

862

AN:

1309860

Hom.:

AF XY:

0.000680

AC XY:

439

AN XY:

645230

show subpopulations

Gnomad4 AFR exome

AF:

0.00103

AC:

AN:

26296

Gnomad4 AMR exome

AF:

0.000195

AC:

AN:

25702

Gnomad4 ASJ exome

AF:

0.0000442

AC:

AN:

22622

Gnomad4 EAS exome

AF:

0.000279

AC:

AN:

28694

Gnomad4 SAS exome

AF:

0.000800

AC:

AN:

71258

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

32382

Gnomad4 NFE exome

AF:

0.000691

AC:

722

AN:

1044664

Gnomad4 Remaining exome

AF:

0.000737

AC:

AN:

54290

Heterozygous variant carriers

149

198

248

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000693

AC:

105

AN:

151540

Hom.:

Cov.:

AF XY:

0.000676

AC XY:

AN XY:

74016

show subpopulations

Gnomad4 AFR

AF:

0.00126

AC:

0.00125549

AN:

0.00125549

Gnomad4 AMR

AF:

0.000262

AC:

0.000262467

AN:

0.000262467

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00166

AC:

0.0016632

AN:

0.0016632

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.000605

AC:

0.000605238

AN:

0.000605238

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000688

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The SPNS2 p.Thr77_Gly79del variant was not identified in the literature nor was it identified in ClinVar. The variant was identified in dbSNP (ID: rs763007985) and in control databases in 65 of 103722 chromosomes at a frequency of 0.0006267 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 11 of 9494 chromosomes (freq: 0.001159), European (non-Finnish) in 36 of 41774 chromosomes (freq: 0.000862), Other in 2 of 3262 chromosomes (freq: 0.000613), South Asian in 9 of 15700 chromosomes (freq: 0.000573), Latino in 6 of 15438 chromosomes (freq: 0.000389) and East Asian in 1 of 4272 chromosomes (freq: 0.000234), but was not observed in the Ashkenazi Jewish or European (Finnish) populations. This variant is an in-frame deletion resulting in the removal codons 77 to 79; the impact of this alteration on SPNS2 protein function is not known. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Mutation Taster

=153/47

polymorphism

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over