rs1555558169

Variant names:

• chr15-76728739-T-C
• rs1555558169
• NM_020843.4:c.2023-2A>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_020843.4(SCAPER):​c.2023-2A>G variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SCAPER NM_020843.4 splice_acceptor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic no assertion criteria provided P:4
• Conservation: PhyloP100: 7.45
• Publications: 4 publications found

Genes affected

SCAPER (HGNC:13081): (S-phase cyclin A associated protein in the ER) Predicted to enable nucleic acid binding activity and zinc ion binding activity. Located in cytosol and nuclear speck. [provided by Alliance of Genome Resources, Apr 2022]

SCAPER Gene-Disease associations (from GenCC):

• intellectual developmental disorder and retinitis pigmentosa; IDDRP

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Bardet-Biedl syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-76728739-T-C is Pathogenic according to our data. Variant chr15-76728739-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 424861.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020843.4. 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
	SCAPER	NM_020843.4	MANE Select	c.2023-2A>G		splice_acceptor intron	N/A	NP_065894.2
	SCAPER	NM_001353009.2		c.2041-2A>G		splice_acceptor intron	N/A	NP_001339938.1
	SCAPER	NM_001353011.2		c.1639-2A>G		splice_acceptor intron	N/A	NP_001339940.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCAPER	ENST00000563290.6	TSL:5 MANE Select	c.2023-2A>G		splice_acceptor intron	N/A	ENSP00000454973.1
	SCAPER	ENST00000324767.11	TSL:1	c.2023-2A>G		splice_acceptor intron	N/A	ENSP00000326924.7
	SCAPER	ENST00000538941.6	TSL:1	c.1285-2A>G		splice_acceptor intron	N/A	ENSP00000442190.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
2	-	-	Intellectual developmental disorder and retinitis pigmentosa; IDDRP (2)
1	-	-	Retinitis pigmentosa (1)
1	-	-	Syndromic retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	30
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.97	D
PhyloP100		7.5
GERP RS		5.1
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.93		Position offset: -2

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

Other links and lift over

dbSNP: rs1555558169; hg19: chr15-77021080;