8-67064342-C-T

Variant names:

• chr8-67064342-C-T
• rs61735315
• ENST00000262210.11:c.-57C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000262210.11(CSPP1):​c.-57C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00811 in 1,577,398 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0068 (10 hom., cov: 31)
  • Exomes 𝑓: 0.0082 (63 hom.)
• Consequence: CSPP1 ENST00000262210.11 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.393
• Publications: 1 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 8-67064342-C-T is Benign according to our data. Variant chr8-67064342-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1212697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00685 (1042/152130) while in subpopulation NFE AF = 0.00952 (647/67976). AF 95% confidence interval is 0.00891. There are 10 homozygotes in GnomAd4. There are 509 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000262210.11. 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.-207C>T		upstream_gene	N/A	NP_001369320.1	A0A7I2V5W3
	CSPP1	NM_001364869.1		c.-57C>T		upstream_gene	N/A	NP_001351798.1	A0A7I2PHE7
	CSPP1	NM_024790.7		c.-57C>T		upstream_gene	N/A	NP_079066.5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSPP1	ENST00000262210.11	TSL:1	c.-57C>T		5_prime_UTR	Exon 1 of 30	ENSP00000262210.6	A0A7I2PHE7
	CSPP1	ENST00000675306.2		c.-207C>T		5_prime_UTR	Exon 1 of 28	ENSP00000502421.1	A0A6Q8PGS3
	CSPP1	ENST00000678017.1		c.-730C>T		5_prime_UTR	Exon 1 of 25	ENSP00000504394.1	A0A7I2V5P5

Frequencies

GnomAD3 genomes AF: 0.00685 AC: 1042 AN: 152012 Hom.: 10 Cov.: 31

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.00550

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.0103

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00952

Gnomad OTH AF: 0.00766

GnomAD4 exome AF: 0.00824 AC: 11745 AN: 1425268 Hom.: 63 Cov.: 29 AF XY: 0.00803 AC XY: 5679 AN XY: 707438

African (AFR) AF: 0.00115 AC: 38 AN: 33040

American (AMR) AF: 0.00325 AC: 130 AN: 40042

Ashkenazi Jewish (ASJ) AF: 0.000279 AC: 7 AN: 25112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39026

South Asian (SAS) AF: 0.00129 AC: 107 AN: 82978

European-Finnish (FIN) AF: 0.00883 AC: 402 AN: 45538

Middle Eastern (MID) AF: 0.00252 AC: 12 AN: 4760

European-Non Finnish (NFE) AF: 0.00976 AC: 10696 AN: 1095706

Other (OTH) AF: 0.00598 AC: 353 AN: 59066

GnomAD4 genome AF: 0.00685 AC: 1042 AN: 152130 Hom.: 10 Cov.: 31 AF XY: 0.00684 AC XY: 509 AN XY: 74378

African (AFR) AF: 0.00135 AC: 56 AN: 41520

American (AMR) AF: 0.00550 AC: 84 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3466

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5150

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4810

European-Finnish (FIN) AF: 0.0103 AC: 109 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00952 AC: 647 AN: 67976

Other (OTH) AF: 0.00758 AC: 16 AN: 2112

Alfa AF: 0.00466 Hom.: 1

Bravo AF: 0.00680

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	9.2
DANN	Benign	0.75
PhyloP100		0.39
PromoterAI		-0.043	Neutral
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: rs61735315; hg19: chr8-67976577;