NM_001382391.1:c.2392-8_2392-4delTTTTA

Variant names:

• chr8-67158977-TTTTTA-T
• rs528357182
• NM_001382391.1:c.2392-8_2392-4delTTTTA

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001382391.1(CSPP1):​c.2392-8_2392-4delTTTTA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000533 in 1,582,104 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00082 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00050 (3 hom.)
• Consequence: CSPP1 NM_001382391.1 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.560
• 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 8-67158977-TTTTTA-T is Benign according to our data. Variant chr8-67158977-TTTTTA-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 372673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000821 (125/152308) while in subpopulation AMR AF = 0.00261 (40/15308). AF 95% confidence interval is 0.00197. There are 0 homozygotes in GnomAd4. There are 77 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001382391.1. 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
	CSPP1	NM_001382391.1	MANE Select	c.2392-8_2392-4delTTTTA		splice_region intron	N/A	NP_001369320.1
	CSPP1	NM_001364869.1		c.2458-8_2458-4delTTTTA		splice_region intron	N/A	NP_001351798.1
	CSPP1	NM_024790.7		c.2377-8_2377-4delTTTTA		splice_region intron	N/A	NP_079066.5

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSPP1	ENST00000678616.1	MANE Select	c.2392-8_2392-4delTTTTA		splice_region intron	N/A	ENSP00000504733.1
	CSPP1	ENST00000262210.11	TSL:1	c.2458-8_2458-4delTTTTA		splice_region intron	N/A	ENSP00000262210.6
	CSPP1	ENST00000519668.1	TSL:1	c.1342-8_1342-4delTTTTA		splice_region intron	N/A	ENSP00000430092.1

Frequencies

GnomAD3 genomes AF: 0.000815 AC: 124 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.000875 AC: 199 AN: 227374 AF XY: 0.000888

Gnomad AFR exome AF: 0.000134

Gnomad AMR exome AF: 0.00102

Gnomad ASJ exome AF: 0.0119

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000437

Gnomad OTH exome AF: 0.00110

GnomAD4 exome AF: 0.000502 AC: 718 AN: 1429796 Hom.: 3 AF XY: 0.000521 AC XY: 371 AN XY: 711562

African (AFR) AF: 0.000735 AC: 23 AN: 31310

American (AMR) AF: 0.000905 AC: 35 AN: 38694

Ashkenazi Jewish (ASJ) AF: 0.0124 AC: 311 AN: 25010

East Asian (EAS) AF: 0.00 AC: 0 AN: 39462

South Asian (SAS) AF: 0.000346 AC: 28 AN: 80992

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 52892

Middle Eastern (MID) AF: 0.00484 AC: 26 AN: 5374

European-Non Finnish (NFE) AF: 0.000200 AC: 219 AN: 1097066

Other (OTH) AF: 0.00127 AC: 75 AN: 58996

GnomAD4 genome AF: 0.000821 AC: 125 AN: 152308 Hom.: 0 Cov.: 32 AF XY: 0.00103 AC XY: 77 AN XY: 74478

African (AFR) AF: 0.000217 AC: 9 AN: 41544

American (AMR) AF: 0.00261 AC: 40 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0141 AC: 49 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68034

Other (OTH) AF: 0.00190 AC: 4 AN: 2108

Alfa AF: 0.00196 Hom.: 1

Bravo AF: 0.000759

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Joubert syndrome 21 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.56
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs528357182; hg19: chr8-68071212;