8-67149947-CTTTTT-C

Variant names:

• chr8-67149947-CTTTTT-C
• rs11296619
• NM_001382391.1:c.2128+32_2128+36delTTTTT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP6_Moderate BS1

The NM_001382391.1(CSPP1):​c.2128+32_2128+36delTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00538 in 1,129,998 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0058 (0 hom.)
• Consequence: CSPP1 NM_001382391.1 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.10
• 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.

• PM2: Variant has high frequency in the SAS (0.0154) population. However there is too low homozygotes in high coverage region: (expected more than 8, got 0).
• BP6: Variant 8-67149947-CTTTTT-C is Benign according to our data. Variant chr8-67149947-CTTTTT-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1213678.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000134 (12/89440) while in subpopulation SAS AF = 0.00357 (9/2518). AF 95% confidence interval is 0.00186. There are 0 homozygotes in GnomAd4. There are 10 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSPP1	NM_001382391.1	c.2128+32_2128+36delTTTTT		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+32_2128+36delTTTTT		intron_variant	Intron 18 of 30		NM_001382391.1	ENSP00000504733.1

Frequencies

GnomAD3 genomes AF: 0.000134 AC: 12 AN: 89468 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00355

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00947 AC: 634 AN: 66916 AF XY: 0.0104

Gnomad AFR exome AF: 0.00706

Gnomad AMR exome AF: 0.0103

Gnomad ASJ exome AF: 0.00811

Gnomad EAS exome AF: 0.00883

Gnomad FIN exome AF: 0.0141

Gnomad NFE exome AF: 0.00763

Gnomad OTH exome AF: 0.00912

GnomAD4 exome AF: 0.00583 AC: 6068 AN: 1040558 Hom.: 0 AF XY: 0.00622 AC XY: 3190 AN XY: 513172

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

African (AFR) AF: 0.00676 AC: 148 AN: 21878

American (AMR) AF: 0.00849 AC: 151 AN: 17776

Ashkenazi Jewish (ASJ) AF: 0.00845 AC: 128 AN: 15154

East Asian (EAS) AF: 0.00883 AC: 255 AN: 28892

South Asian (SAS) AF: 0.0164 AC: 699 AN: 42732

European-Finnish (FIN) AF: 0.0107 AC: 381 AN: 35732

Middle Eastern (MID) AF: 0.00434 AC: 14 AN: 3226

European-Non Finnish (NFE) AF: 0.00483 AC: 4017 AN: 832518

Other (OTH) AF: 0.00645 AC: 275 AN: 42650

⚠️ 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: 0.000134 AC: 12 AN: 89440 Hom.: 0 Cov.: 0 AF XY: 0.000243 AC XY: 10 AN XY: 41160

African (AFR) AF: 0.000130 AC: 3 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: 0.00357 AC: 9 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: 45366

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

Alfa AF: 0.00 Hom.: 1063

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Dec 01, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.1
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: rs11296619; hg19: chr8-68062182;