8-67103140-A-G

Variant names:

• chr8-67103140-A-G
• rs797045503
• NM_001382391.1:c.1022+5A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001382391.1(CSPP1):​c.1022+5A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000294 in 1,362,272 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: CSPP1 NM_001382391.1 splice_region, intron
• Scores: Splicing: ADA: 0.0003405
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.840
• Publications: 0 publications found

Genes affected

CSPP1 (HGNC:26193): (centrosome and spindle pole associated protein 1) This gene encodes a centrosome and spindle pole associated protein. The encoded protein plays a role in cell-cycle progression and spindle organization, regulates cytokinesis, interacts with Nephrocystin 8 and is required for cilia formation. Mutations in this gene result in primary cilia abnormalities and classical Joubert syndrome. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Apr 2014]

CSPP1 Gene-Disease associations (from GenCC):

• Joubert syndrome 21

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• Joubert syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Joubert syndrome with Jeune asphyxiating thoracic dystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Meckel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSPP1	NM_001382391.1	c.1022+5A>G		splice_region_variant, intron_variant	Intron 8 of 30	ENST00000678616.1	NP_001369320.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSPP1	ENST00000678616.1	c.1022+5A>G		splice_region_variant, intron_variant	Intron 8 of 30		NM_001382391.1	ENSP00000504733.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000407 AC: 1 AN: 245808 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000896

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000294 AC: 4 AN: 1362272 Hom.: 0 Cov.: 21 AF XY: 0.00000293 AC XY: 2 AN XY: 683422

African (AFR) AF: 0.00 AC: 0 AN: 31454

American (AMR) AF: 0.00 AC: 0 AN: 44300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25444

East Asian (EAS) AF: 0.00 AC: 0 AN: 39084

South Asian (SAS) AF: 0.00 AC: 0 AN: 83780

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52918

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5570

European-Non Finnish (NFE) AF: 0.00000391 AC: 4 AN: 1022658

Other (OTH) AF: 0.00 AC: 0 AN: 57064

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	23
DANN	Benign	0.83
PhyloP100		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00034
dbscSNV1_RF	Benign	0.046
SpliceAI score (max)		0.39		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.39		Position offset: 0

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

Other links and lift over

dbSNP: rs797045503; hg19: chr8-68015375;