Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001382391.1(CSPP1):c.1693G>A(p.Val565Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00164 in 1,602,522 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00094 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 4 hom. )

Consequence

CSPP1
NM_001382391.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: -1.42

Publications

5 publications found

Variant links:

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

CSPP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0046307743).

BP6

Variant 8-67118817-G-A is Benign according to our data. Variant chr8-67118817-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 449196.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00094 (143/152166) while in subpopulation NFE AF = 0.00159 (108/67954). AF 95% confidence interval is 0.00135. There are 0 homozygotes in GnomAd4. There are 50 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001382391.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CSPP1	NM_001382391.1	MANE Select	c.1693G>A	p.Val565Ile	missense	Exon 15 of 31	NP_001369320.1
CSPP1	NM_001364869.1		c.1759G>A	p.Val587Ile	missense	Exon 14 of 30	NP_001351798.1
CSPP1	NM_024790.7		c.1678G>A	p.Val560Ile	missense	Exon 13 of 29	NP_079066.5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CSPP1	ENST00000678616.1	MANE Select	c.1693G>A	p.Val565Ile	missense	Exon 15 of 31	ENSP00000504733.1
CSPP1	ENST00000262210.11	TSL:1	c.1759G>A	p.Val587Ile	missense	Exon 14 of 30	ENSP00000262210.6
CSPP1	ENST00000519668.1	TSL:1	c.796G>A	p.Val266Ile	missense	Exon 11 of 26	ENSP00000430092.1

Frequencies

GnomAD3 genomes

AF:

0.000940

AC:

143

AN:

152048

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.000393

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:

0.00159

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.000938

AC:

233

AN:

248374

AF XY:

0.000839

show subpopulations

Gnomad AFR exome

AF:

0.000713

Gnomad AMR exome

AF:

0.000669

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000931

Gnomad NFE exome

AF:

0.00172

Gnomad OTH exome

AF:

0.000498

GnomAD4 exome

AF:

0.00172

AC:

2491

AN:

1450356

Hom.:

Cov.:

AF XY:

0.00158

AC XY:

1144

AN XY:

722278

show subpopulations

African (AFR)

AF:

0.000481

AC:

AN:

33244

American (AMR)

AF:

0.000627

AC:

AN:

44660

Ashkenazi Jewish (ASJ)

AF:

0.0000769

AC:

AN:

26016

East Asian (EAS)

AF:

0.00

AC:

AN:

39596

South Asian (SAS)

AF:

0.0000116

AC:

AN:

85902

European-Finnish (FIN)

AF:

0.0000750

AC:

AN:

53312

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00213

AC:

2342

AN:

1101892

Other (OTH)

AF:

0.00163

AC:

AN:

59974

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

101

201

302

402

503

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

192

288

384

480

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000940

AC:

143

AN:

152166

Hom.:

Cov.:

AF XY:

0.000672

AC XY:

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.000385

AC:

AN:

41540

American (AMR)

AF:

0.000393

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00159

AC:

108

AN:

67954

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00137

Hom.:

Bravo

AF:

0.00107

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000545

AC:

ESP6500EA

AF:

0.00135

AC:

ExAC

AF:

0.000811

AC:

EpiCase

AF:

0.00153

EpiControl

AF:

0.00154

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

CSPP1-related disorder (1)

Joubert syndrome 21 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.0030

(source)

DANN

Benign

0.17

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0066

LIST_S2

Benign

0.43

M_CAP

Benign

0.0030

MetaRNN

Benign

0.0046

MetaSVM

Benign

-0.97

PhyloP100

-1.4

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.17

REVEL

Benign

0.017

Sift

Benign

0.81

Sift4G

Benign

0.32

Polyphen

0.0

Vest4

0.11

MVP

0.20

MPC

0.098

ClinPred

0.0042

GERP RS

-7.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.075

Mutation Taster

=97/3

polymorphism

(source)

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

Publications

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rs199608505

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over