8-67064422-C-G

Variant names:

• chr8-67064422-C-G
• rs988655476
• ENST00000262210.11:c.24C>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_001364869.1(CSPP1):​c.24C>G​(p.Ala8Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: CSPP1 NM_001364869.1 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.92
• 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]

COPS5 (HGNC:2240): (COP9 signalosome subunit 5) The protein encoded by this gene is one of the eight subunits of COP9 signalosome, a highly conserved protein complex that functions as an important regulator in multiple signaling pathways. The structure and function of COP9 signalosome is similar to that of the 19S regulatory particle of 26S proteasome. COP9 signalosome has been shown to interact with SCF-type E3 ubiquitin ligases and act as a positive regulator of E3 ubiquitin ligases. This protein is reported to be involved in the degradation of cyclin-dependent kinase inhibitor CDKN1B/p27Kip1. It is also known to be an coactivator that increases the specificity of JUN/AP1 transcription factors. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 8-67064422-C-G is Benign according to our data. Variant chr8-67064422-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3710123.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.92 with no splicing effect.

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.-127C>G		5_prime_UTR	Exon 1 of 31	NP_001369320.1	A0A7I2V5W3
	CSPP1	NM_001364869.1		c.24C>G	p.Ala8Ala	synonymous	Exon 1 of 30	NP_001351798.1	A0A7I2PHE7
	CSPP1	NM_024790.7		c.24C>G	p.Ala8Ala	synonymous	Exon 1 of 29	NP_079066.5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSPP1	ENST00000262210.11	TSL:1	c.24C>G	p.Ala8Ala	synonymous	Exon 1 of 30	ENSP00000262210.6	A0A7I2PHE7
	CSPP1	ENST00000678616.1	MANE Select	c.-127C>G		5_prime_UTR	Exon 1 of 31	ENSP00000504733.1	A0A7I2V5W3
	CSPP1	ENST00000676605.1		c.24C>G	p.Ala8Ala	synonymous	Exon 1 of 30	ENSP00000503605.1	A0A7I2V3V5

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152170 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248646 AF XY: 0.00000741

Gnomad AFR exome AF: 0.0000647

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461574 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727122

African (AFR) AF: 0.0000598 AC: 2 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111872

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152170 Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3 AN XY: 74322

African (AFR) AF: 0.0000965 AC: 4 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

ClinVar

ClinVar submissions

Significance: Likely 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
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.76
DANN	Benign	0.46
PhyloP100		-1.9
PromoterAI		0.078	Neutral

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: rs988655476; hg19: chr8-67976657; COSMIC: COSV51583853; COSMIC: COSV51583853;