8-67149947-CTTTTTTTTTTTTTTT-CTTTTTTTTTTT

Variant names:

• chr8-67149947-CTTTT-C
• rs11296619
• NM_001382391.1:c.2128+33_2128+36delTTTT

Variant summary

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

The NM_001364869.1(CSPP1):​c.2194+33_2194+36delTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0275 in 1,108,126 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 0)
  • Exomes 𝑓: 0.030 (0 hom.)
• Consequence: CSPP1 NM_001364869.1 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Variant has high frequency in the SAS (0.0474) population. However there is too low homozygotes in high coverage region: (expected more than 208, got 0).
• BP6: Variant 8-67149947-CTTTT-C is Benign according to our data. Variant chr8-67149947-CTTTT-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1219474.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00101 (90/89440) while in subpopulation SAS AF = 0.0322 (81/2518). AF 95% confidence interval is 0.0265. There are 0 homozygotes in GnomAd4. There are 70 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+33_2128+36delTTTT		intron	N/A	NP_001369320.1
	CSPP1	NM_001364869.1		c.2194+33_2194+36delTTTT		intron	N/A	NP_001351798.1
	CSPP1	NM_024790.7		c.2113+33_2113+36delTTTT		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+16delTTTT		intron	N/A	ENSP00000504733.1
	CSPP1	ENST00000262210.11	TSL:1	c.2194+13_2194+16delTTTT		intron	N/A	ENSP00000262210.6
	CSPP1	ENST00000519668.1	TSL:1	c.1079-4076_1079-4073delTTTT		intron	N/A	ENSP00000430092.1

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 90 AN: 89468 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000260

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0320

Gnomad FIN AF: 0.000340

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000220

Gnomad OTH AF: 0.000858

GnomAD2 exomes AF: 0.0312 AC: 2091 AN: 66916 AF XY: 0.0327

Gnomad AFR exome AF: 0.0286

Gnomad AMR exome AF: 0.0400

Gnomad ASJ exome AF: 0.0272

Gnomad EAS exome AF: 0.0322

Gnomad FIN exome AF: 0.0445

Gnomad NFE exome AF: 0.0263

Gnomad OTH exome AF: 0.0344

GnomAD4 exome AF: 0.0298 AC: 30335 AN: 1018686 Hom.: 0 AF XY: 0.0308 AC XY: 15482 AN XY: 502118

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

African (AFR) AF: 0.0343 AC: 735 AN: 21428

American (AMR) AF: 0.0392 AC: 674 AN: 17206

Ashkenazi Jewish (ASJ) AF: 0.0367 AC: 543 AN: 14780

East Asian (EAS) AF: 0.0396 AC: 1115 AN: 28124

South Asian (SAS) AF: 0.0491 AC: 2069 AN: 42096

European-Finnish (FIN) AF: 0.0468 AC: 1634 AN: 34946

Middle Eastern (MID) AF: 0.0332 AC: 105 AN: 3166

European-Non Finnish (NFE) AF: 0.0270 AC: 22045 AN: 815294

Other (OTH) AF: 0.0340 AC: 1415 AN: 41646

⚠️ 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: 0.00101 AC: 90 AN: 89440 Hom.: 0 Cov.: 0 AF XY: 0.00170 AC XY: 70 AN XY: 41162

African (AFR) AF: 0.000260 AC: 6 AN: 23114

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: 0.0322 AC: 81 AN: 2518

European-Finnish (FIN) AF: 0.000340 AC: 1 AN: 2940

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

European-Non Finnish (NFE) AF: 0.0000220 AC: 1 AN: 45368

Other (OTH) AF: 0.000855 AC: 1 AN: 1170

Alfa AF: 0.00 Hom.: 1063

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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;