chr8-67149947-CTTTTTTTT-C

Variant names:

• chr8-67149947-CTTTTTTTT-C
• rs11296619
• NM_001382391.1:c.2128+29_2128+36delTTTTTTTT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_001364869.1(CSPP1):​c.2194+29_2194+36delTTTTTTTT variant causes a intron change. The variant allele was found at a frequency of 0.0000799 in 1,139,054 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00012 (1 hom., cov: 0)
  • Exomes 𝑓: 0.000076 (0 hom.)
• Consequence: CSPP1 NM_001364869.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.17
• 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: Likely_benign. The variant received -4 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000123 (11/89444) while in subpopulation SAS AF = 0.00238 (6/2518). AF 95% confidence interval is 0.00104. There are 1 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001364869.1. 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
	CSPP1	NM_001382391.1	MANE Select	c.2128+29_2128+36delTTTTTTTT		intron	N/A	NP_001369320.1
	CSPP1	NM_001364869.1		c.2194+29_2194+36delTTTTTTTT		intron	N/A	NP_001351798.1
	CSPP1	NM_024790.7		c.2113+29_2113+36delTTTTTTTT		intron	N/A	NP_079066.5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSPP1	ENST00000678616.1	MANE Select	c.2128+13_2128+20delTTTTTTTT		intron	N/A	ENSP00000504733.1
	CSPP1	ENST00000262210.11	TSL:1	c.2194+13_2194+20delTTTTTTTT		intron	N/A	ENSP00000262210.6
	CSPP1	ENST00000519668.1	TSL:1	c.1079-4076_1079-4069delTTTTTTTT		intron	N/A	ENSP00000430092.1

Frequencies

GnomAD3 genomes AF: 0.000123 AC: 11 AN: 89472 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00237

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000762 AC: 80 AN: 1049610 Hom.: 0 AF XY: 0.0000908 AC XY: 47 AN XY: 517882

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 22098

American (AMR) AF: 0.00 AC: 0 AN: 17996

Ashkenazi Jewish (ASJ) AF: 0.0000651 AC: 1 AN: 15354

East Asian (EAS) AF: 0.0000342 AC: 1 AN: 29244

South Asian (SAS) AF: 0.000672 AC: 29 AN: 43162

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36256

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3248

European-Non Finnish (NFE) AF: 0.0000512 AC: 43 AN: 839172

Other (OTH) AF: 0.000139 AC: 6 AN: 43080

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000123 AC: 11 AN: 89444 Hom.: 1 Cov.: 0 AF XY: 0.000121 AC XY: 5 AN XY: 41164

African (AFR) AF: 0.000216 AC: 5 AN: 23116

American (AMR) AF: 0.00 AC: 0 AN: 8028

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2460

East Asian (EAS) AF: 0.00 AC: 0 AN: 3100

South Asian (SAS) AF: 0.00238 AC: 6 AN: 2518

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2940

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 142

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 45370

Other (OTH) AF: 0.00 AC: 0 AN: 1170

Alfa AF: 0.00 Hom.: 1063

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.2

Splicing

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

Other links and lift over

dbSNP: rs11296619; hg19: chr8-68062182;