dbSNP rs114177619: CSPP1:p.Thr659Thr (chr8-67149784-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001364869.1(CSPP1):c.2043T>C(p.Thr681Thr) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00136 in 1,534,256 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0078 ( 13 hom., cov: 32)

Exomes 𝑓: 0.00066 ( 12 hom. )

Consequence

CSPP1
NM_001364869.1 splice_region, synonymous

Scores

Splicing: ADA: 0.001318

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.16

Publications

0 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP6

Variant 8-67149784-T-C is Benign according to our data. Variant chr8-67149784-T-C is described in ClinVar as Benign. ClinVar VariationId is 474852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.16 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00776 (1182/152232) while in subpopulation AFR AF = 0.0271 (1127/41542). AF 95% confidence interval is 0.0258. There are 13 homozygotes in GnomAd4. There are 553 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 13 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CSPP1	NM_001382391.1	MANE Select	c.1977T>C	p.Thr659Thr	splice_region synonymous	Exon 18 of 31	NP_001369320.1
CSPP1	NM_001364869.1		c.2043T>C	p.Thr681Thr	splice_region synonymous	Exon 17 of 30	NP_001351798.1
CSPP1	NM_024790.7		c.1962T>C	p.Thr654Thr	splice_region synonymous	Exon 16 of 29	NP_079066.5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CSPP1	ENST00000678616.1	MANE Select	c.1977T>C	p.Thr659Thr	splice_region synonymous	Exon 18 of 31	ENSP00000504733.1
CSPP1	ENST00000262210.11	TSL:1	c.2043T>C	p.Thr681Thr	splice_region synonymous	Exon 17 of 30	ENSP00000262210.6
CSPP1	ENST00000519668.1	TSL:1	c.1079-4240T>C		intron	N/A	ENSP00000430092.1

Frequencies

GnomAD3 genomes

AF:

0.00774

AC:

1178

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0271

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00767

GnomAD2 exomes

AF:

0.00189

AC:

375

AN:

198118

AF XY:

0.00150

show subpopulations

Gnomad AFR exome

AF:

0.0278

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000205

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000660

AC:

912

AN:

1382024

Hom.:

Cov.:

AF XY:

0.000611

AC XY:

419

AN XY:

685634

show subpopulations

African (AFR)

AF:

0.0271

AC:

799

AN:

29486

American (AMR)

AF:

0.000913

AC:

AN:

29574

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23002

East Asian (EAS)

AF:

0.0000270

AC:

AN:

37022

South Asian (SAS)

AF:

0.0000281

AC:

AN:

71192

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51446

Middle Eastern (MID)

AF:

0.000556

AC:

AN:

5400

European-Non Finnish (NFE)

AF:

0.00000371

AC:

AN:

1078316

Other (OTH)

AF:

0.00134

AC:

AN:

56586

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

116

155

194

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<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:

0.00776

AC:

1182

AN:

152232

Hom.:

Cov.:

AF XY:

0.00743

AC XY:

553

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.0271

AC:

1127

AN:

41542

American (AMR)

AF:

0.00216

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68022

Other (OTH)

AF:

0.00759

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

113

169

226

282

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00303

Hom.:

Bravo

AF:

0.00844

Asia WGS

AF:

0.00145

AC:

AN:

3472

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Joubert syndrome 21 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.65

PhyloP100

2.2

Mutation Taster

=63/37

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0013

dbscSNV1_RF

Benign

0.080

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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

Computational scores

Splicing

Publications

Other links and lift over