8-67149947-CTTTTTTTTTTTTTTT-CTTTTTTTTTTTTT

Variant names:

• chr8-67149947-CTT-C
• rs11296619
• NM_001382391.1:c.2128+35_2128+36delTT

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+35_2128+36delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.243 in 1,022,998 control chromosomes in the GnomAD database, including 62 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (67 hom., cov: 0)
  • Exomes 𝑓: 0.24 (62 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-CTT-C is Benign according to our data. Variant chr8-67149947-CTT-C is described in ClinVar as Benign. ClinVar VariationId is 1249598.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 62 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSPP1	NM_001382391.1	c.2128+35_2128+36delTT		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+35_2128+36delTT		intron_variant	Intron 18 of 30		NM_001382391.1	ENSP00000504733.1

Frequencies

GnomAD3 genomes AF: 0.0362 AC: 3240 AN: 89574 Hom.: 67 Cov.: 0

Gnomad AFR AF: 0.0190

Gnomad AMI AF: 0.00167

Gnomad AMR AF: 0.0269

Gnomad ASJ AF: 0.0304

Gnomad EAS AF: 0.00353

Gnomad SAS AF: 0.0138

Gnomad FIN AF: 0.0936

Gnomad MID AF: 0.0375

Gnomad NFE AF: 0.0475

Gnomad OTH AF: 0.0206

GnomAD2 exomes AF: 0.0930 AC: 6220 AN: 66916 AF XY: 0.0922

Gnomad AFR exome AF: 0.113

Gnomad AMR exome AF: 0.140

Gnomad ASJ exome AF: 0.111

Gnomad EAS exome AF: 0.0990

Gnomad FIN exome AF: 0.0959

Gnomad NFE exome AF: 0.0779

Gnomad OTH exome AF: 0.103

GnomAD4 exome AF: 0.243 AC: 248622 AN: 1022998 Hom.: 62 AF XY: 0.240 AC XY: 120961 AN XY: 504828

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

African (AFR) AF: 0.231 AC: 4973 AN: 21532

American (AMR) AF: 0.161 AC: 2852 AN: 17726

Ashkenazi Jewish (ASJ) AF: 0.228 AC: 3444 AN: 15086

East Asian (EAS) AF: 0.208 AC: 5944 AN: 28550

South Asian (SAS) AF: 0.200 AC: 8491 AN: 42392

European-Finnish (FIN) AF: 0.166 AC: 5927 AN: 35616

Middle Eastern (MID) AF: 0.213 AC: 677 AN: 3182

European-Non Finnish (NFE) AF: 0.252 AC: 206185 AN: 816840

Other (OTH) AF: 0.241 AC: 10129 AN: 42074

⚠️ 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: 0.0362 AC: 3240 AN: 89546 Hom.: 67 Cov.: 0 AF XY: 0.0380 AC XY: 1566 AN XY: 41216

African (AFR) AF: 0.0190 AC: 440 AN: 23130

American (AMR) AF: 0.0269 AC: 216 AN: 8032

Ashkenazi Jewish (ASJ) AF: 0.0304 AC: 75 AN: 2464

East Asian (EAS) AF: 0.00355 AC: 11 AN: 3100

South Asian (SAS) AF: 0.0143 AC: 36 AN: 2518

European-Finnish (FIN) AF: 0.0936 AC: 276 AN: 2950

Middle Eastern (MID) AF: 0.0282 AC: 4 AN: 142

European-Non Finnish (NFE) AF: 0.0475 AC: 2157 AN: 45440

Other (OTH) AF: 0.0205 AC: 24 AN: 1170

Alfa AF: 0.0471 Hom.: 1063

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Joubert syndrome 21 Benign:1

Sep 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Sep 02, 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; COSMIC: COSV107263080;