8-67064428-A-G

Variant names:

• chr8-67064428-A-G
• rs181470846
• ENST00000262210.11:c.30A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001364869.1(CSPP1):​c.30A>G​(p.Val10Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00693 in 1,613,876 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V10V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0046 (5 hom., cov: 31)
  • Exomes 𝑓: 0.0072 (41 hom.)
• Consequence: CSPP1 NM_001364869.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.05
• Publications: 2 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 8-67064428-A-G is Benign according to our data. Variant chr8-67064428-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 379431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.05 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00461 (702/152248) while in subpopulation NFE AF = 0.00804 (547/68002). AF 95% confidence interval is 0.00749. There are 5 homozygotes in GnomAd4. There are 305 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

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.-121A>G		5_prime_UTR	Exon 1 of 31	NP_001369320.1	A0A7I2V5W3
	CSPP1	NM_001364869.1		c.30A>G	p.Val10Val	synonymous	Exon 1 of 30	NP_001351798.1	A0A7I2PHE7
	CSPP1	NM_024790.7		c.30A>G	p.Val10Val	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.30A>G	p.Val10Val	synonymous	Exon 1 of 30	ENSP00000262210.6	A0A7I2PHE7
	CSPP1	ENST00000678616.1	MANE Select	c.-121A>G		5_prime_UTR	Exon 1 of 31	ENSP00000504733.1	A0A7I2V5W3
	CSPP1	ENST00000676605.1		c.30A>G	p.Val10Val	synonymous	Exon 1 of 30	ENSP00000503605.1	A0A7I2V3V5

Frequencies

GnomAD3 genomes AF: 0.00462 AC: 703 AN: 152132 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.00154

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00806

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00466 AC: 1159 AN: 248848 AF XY: 0.00443

Gnomad AFR exome AF: 0.00162

Gnomad AMR exome AF: 0.00128

Gnomad ASJ exome AF: 0.0115

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00196

Gnomad NFE exome AF: 0.00772

Gnomad OTH exome AF: 0.00529

GnomAD4 exome AF: 0.00717 AC: 10480 AN: 1461628 Hom.: 41 Cov.: 31 AF XY: 0.00699 AC XY: 5085 AN XY: 727154

African (AFR) AF: 0.00122 AC: 41 AN: 33472

American (AMR) AF: 0.00130 AC: 58 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0123 AC: 321 AN: 26120

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

South Asian (SAS) AF: 0.00111 AC: 96 AN: 86254

European-Finnish (FIN) AF: 0.00219 AC: 117 AN: 53346

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00851 AC: 9467 AN: 1111874

Other (OTH) AF: 0.00628 AC: 379 AN: 60380

GnomAD4 genome AF: 0.00461 AC: 702 AN: 152248 Hom.: 5 Cov.: 31 AF XY: 0.00410 AC XY: 305 AN XY: 74448

African (AFR) AF: 0.00154 AC: 64 AN: 41544

American (AMR) AF: 0.00124 AC: 19 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 45 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4830

European-Finnish (FIN) AF: 0.00141 AC: 15 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00804 AC: 547 AN: 68002

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00730 Hom.: 3

Bravo AF: 0.00465

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00556

EpiControl AF: 0.00652

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	CSPP1-related disorder (1)
-	-	1	Joubert syndrome 21 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.2
DANN	Benign	0.31
PhyloP100		-1.0
PromoterAI		0.066	Neutral
Mutation Taster		=95/5	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: rs181470846; hg19: chr8-67976663;