8-67149947-CTTTTTTTTTTTTTTT-CTTTTTTTTTTTT

Variant names:

• chr8-67149947-CTTT-C
• rs11296619
• NM_001382391.1:c.2128+34_2128+36delTTT

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_001382391.1(CSPP1):​c.2128+34_2128+36delTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 989,022 control chromosomes in the GnomAD database, including 6 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (31 hom., cov: 0)
  • Exomes 𝑓: 0.12 (6 hom.)
  • Failed GnomAD Quality Control
• Consequence: CSPP1 NM_001382391.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0650
• 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 -12 ACMG points.

• BP6: Variant 8-67149947-CTTT-C is Benign according to our data. Variant chr8-67149947-CTTT-C is described in ClinVar as Benign. ClinVar VariationId is 1277073.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSPP1	NM_001382391.1	c.2128+34_2128+36delTTT		intron_variant	Intron 18 of 30	ENST00000678616.1	NP_001369320.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSPP1	ENST00000678616.1	c.2128+34_2128+36delTTT		intron_variant	Intron 18 of 30		NM_001382391.1	ENSP00000504733.1

Frequencies

GnomAD3 genomes AF: 0.0194 AC: 1732 AN: 89468 Hom.: 31 Cov.: 0

Gnomad AFR AF: 0.0351

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0139

Gnomad ASJ AF: 0.00773

Gnomad EAS AF: 0.0193

Gnomad SAS AF: 0.0300

Gnomad FIN AF: 0.110

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.00668

Gnomad OTH AF: 0.0180

GnomAD2 exomes AF: 0.0658 AC: 4402 AN: 66916 AF XY: 0.0673

Gnomad AFR exome AF: 0.0739

Gnomad AMR exome AF: 0.106

Gnomad ASJ exome AF: 0.0637

Gnomad EAS exome AF: 0.0762

Gnomad FIN exome AF: 0.0739

Gnomad NFE exome AF: 0.0549

Gnomad OTH exome AF: 0.0701

GnomAD4 exome AF: 0.119 AC: 117995 AN: 989022 Hom.: 6 AF XY: 0.120 AC XY: 58627 AN XY: 487730

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

African (AFR) AF: 0.124 AC: 2574 AN: 20726

American (AMR) AF: 0.116 AC: 1972 AN: 17034

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 1970 AN: 14434

East Asian (EAS) AF: 0.134 AC: 3684 AN: 27396

South Asian (SAS) AF: 0.125 AC: 5212 AN: 41634

European-Finnish (FIN) AF: 0.123 AC: 4241 AN: 34562

Middle Eastern (MID) AF: 0.115 AC: 357 AN: 3104

European-Non Finnish (NFE) AF: 0.118 AC: 92868 AN: 789518

Other (OTH) AF: 0.126 AC: 5117 AN: 40614

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.0193 AC: 1727 AN: 89440 Hom.: 31 Cov.: 0 AF XY: 0.0228 AC XY: 938 AN XY: 41154

African (AFR) AF: 0.0350 AC: 810 AN: 23128

American (AMR) AF: 0.0138 AC: 111 AN: 8030

Ashkenazi Jewish (ASJ) AF: 0.00773 AC: 19 AN: 2458

East Asian (EAS) AF: 0.0191 AC: 59 AN: 3096

South Asian (SAS) AF: 0.0298 AC: 75 AN: 2518

European-Finnish (FIN) AF: 0.110 AC: 323 AN: 2940

Middle Eastern (MID) AF: 0.0423 AC: 6 AN: 142

European-Non Finnish (NFE) AF: 0.00668 AC: 303 AN: 45358

Other (OTH) AF: 0.0179 AC: 21 AN: 1170

Alfa AF: 0.00782 Hom.: 1063

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Joubert syndrome 21 Benign:1

Nov 07, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Aug 18, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.065
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs11296619; hg19: chr8-68062182;