NM_020843.4:c.4099+2T>C

Variant names:

• chr15-76351235-A-G
• NM_020843.4:c.4099+2T>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_020843.4(SCAPER):​c.4099+2T>C variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.000000687 in 1,455,916 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SCAPER NM_020843.4 splice_donor, intron
• Scores: Splicing: ADA: 0.9730
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.25
• Publications: 0 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• neurodevelopmental disorder

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia
• 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 10 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

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCAPER	NM_020843.4	MANE Select	c.4099+2T>C		splice_donor intron	N/A	NP_065894.2	Q9BY12-1
	SCAPER	NM_001353009.2		c.4117+2T>C		splice_donor intron	N/A	NP_001339938.1
	SCAPER	NM_001353011.2		c.3715+2T>C		splice_donor intron	N/A	NP_001339940.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCAPER	ENST00000563290.6	TSL:5 MANE Select	c.4099+2T>C		splice_donor intron	N/A	ENSP00000454973.1	Q9BY12-1
	SCAPER	ENST00000324767.11	TSL:1	c.4099+2T>C		splice_donor intron	N/A	ENSP00000326924.7	Q9BY12-1
	SCAPER	ENST00000538941.6	TSL:1	c.3361+2T>C		splice_donor intron	N/A	ENSP00000442190.2	Q9BY12-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455916 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 723770

African (AFR) AF: 0.00 AC: 0 AN: 33340

American (AMR) AF: 0.00 AC: 0 AN: 44022

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25976

East Asian (EAS) AF: 0.00 AC: 0 AN: 39536

South Asian (SAS) AF: 0.00 AC: 0 AN: 84762

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53236

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1109114

Other (OTH) AF: 0.00 AC: 0 AN: 60164

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	26
DANN	Uncertain	0.99
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		6.2
GERP RS		5.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Benign	0.68
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.21		Position offset: 2

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

Other links and lift over

hg19: chr15-76643576;