chr8-67149947-CTTTTTTTTTTTT-C

Variant names:

• chr8-67149947-CTTTTTTTTTTTT-C
• rs11296619
• NM_001382391.1:c.2128+25_2128+36delTTTTTTTTTTTT

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS1

The NM_001364869.1(CSPP1):​c.2194+25_2194+36delTTTTTTTTTTTT variant causes a intron change. The variant allele was found at a frequency of 0.000127 in 1,049,692 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00013 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CSPP1 NM_001364869.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 -6 ACMG points.

• BP6: Variant 8-67149947-CTTTTTTTTTTTT-C is Benign according to our data. Variant chr8-67149947-CTTTTTTTTTTTT-C is described in ClinVar as Benign. ClinVar VariationId is 1625493.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.000127 (133/1049692) while in subpopulation AFR AF = 0.00439 (97/22098). AF 95% confidence interval is 0.00368. There are 0 homozygotes in GnomAdExome4. There are 60 alleles in the male GnomAdExome4 subpopulation. 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+25_2128+36delTTTTTTTTTTTT		intron	N/A	NP_001369320.1
	CSPP1	NM_001364869.1		c.2194+25_2194+36delTTTTTTTTTTTT		intron	N/A	NP_001351798.1
	CSPP1	NM_024790.7		c.2113+25_2113+36delTTTTTTTTTTTT		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+24delTTTTTTTTTTTT		intron	N/A	ENSP00000504733.1
	CSPP1	ENST00000262210.11	TSL:1	c.2194+13_2194+24delTTTTTTTTTTTT		intron	N/A	ENSP00000262210.6
	CSPP1	ENST00000519668.1	TSL:1	c.1079-4076_1079-4065delTTTTTTTTTTTT		intron	N/A	ENSP00000430092.1

Frequencies

GnomAD3 genomes AF: 0.00178 AC: 159 AN: 89472 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00619

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00172

GnomAD4 exome AF: 0.000127 AC: 133 AN: 1049692 Hom.: 0 AF XY: 0.000116 AC XY: 60 AN XY: 517928

African (AFR) AF: 0.00439 AC: 97 AN: 22098

American (AMR) AF: 0.000444 AC: 8 AN: 17998

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15356

East Asian (EAS) AF: 0.00 AC: 0 AN: 29252

South Asian (SAS) AF: 0.00 AC: 0 AN: 43176

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

Middle Eastern (MID) AF: 0.000616 AC: 2 AN: 3246

European-Non Finnish (NFE) AF: 0.00000715 AC: 6 AN: 839220

Other (OTH) AF: 0.000464 AC: 20 AN: 43090

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00178 AC: 159 AN: 89444 Hom.: 0 Cov.: 0 AF XY: 0.00209 AC XY: 86 AN XY: 41164

African (AFR) AF: 0.00619 AC: 143 AN: 23116

American (AMR) AF: 0.00137 AC: 11 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: 0.00 AC: 0 AN: 2518

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

Middle Eastern (MID) AF: 0.00704 AC: 1 AN: 142

European-Non Finnish (NFE) AF: 0.0000441 AC: 2 AN: 45370

Other (OTH) AF: 0.00171 AC: 2 AN: 1170

Alfa AF: 0.00 Hom.: 1063

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Joubert syndrome 21 (1)

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;