rs770066826

Variant names:

• chr8-67172474-C-G
• rs770066826
• NM_001382391.1:c.2887C>G

Your query was ambiguous. Multiple possible variants found:

• chr8-67172474-C-G
• chr8-67172474-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001364869.1(CSPP1):​c.2953C>G​(p.Pro985Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P985S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CSPP1 NM_001364869.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.75
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.2887C>G	p.Pro963Ala	missense	Exon 25 of 31	NP_001369320.1
	CSPP1	NM_001364869.1		c.2953C>G	p.Pro985Ala	missense	Exon 24 of 30	NP_001351798.1
	CSPP1	NM_024790.7		c.2872C>G	p.Pro958Ala	missense	Exon 23 of 29	NP_079066.5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSPP1	ENST00000678616.1	MANE Select	c.2887C>G	p.Pro963Ala	missense	Exon 25 of 31	ENSP00000504733.1
	CSPP1	ENST00000262210.11	TSL:1	c.2953C>G	p.Pro985Ala	missense	Exon 24 of 30	ENSP00000262210.6
	CSPP1	ENST00000519668.1	TSL:1	c.1837C>G	p.Pro613Ala	missense	Exon 20 of 26	ENSP00000430092.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

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
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0072	T
MetaRNN	Uncertain	0.67	D
MetaSVM	Benign	-1.0	T
PhyloP100		2.8
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.13
Sift	Benign	0.071	T
Sift4G	Benign	0.066	T
Polyphen		0.99	D
Vest4		0.66
MVP		0.61
MPC		0.57
ClinPred		0.97	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.064
Mutation Taster		=78/22	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: rs770066826; hg19: chr8-68084709;