rs376549634

chr8-67158499-C-Achr8-67158499-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_001382391.1(CSPP1):c.2294C>A(p.Ala765Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000062 in 1,612,126 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A765A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000051 (0 hom.)
• Consequence: CSPP1 NM_001382391.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.55

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.012444794).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000171 (26/151948) while in subpopulation AMR AF= 0.00118 (18/15258). AF 95% confidence interval is 0.000762. There are 0 homozygotes in gnomad4. There are 16 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CSPP1	NM_001382391.1	c.2294C>A	p.Ala765Glu	missense_variant	20/31	ENST00000678616.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSPP1	ENST00000678616.1	c.2294C>A	p.Ala765Glu	missense_variant	20/31		NM_001382391.1

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 151828 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

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: 0.00

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000121 AC: 30 AN: 248000 Hom.: 0 AF XY: 0.000126 AC XY: 17 AN XY: 134636

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.000611

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000445

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.0000507 AC: 74 AN: 1460178 Hom.: 0 Cov.: 30 AF XY: 0.0000496 AC XY: 36 AN XY: 726330

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000762

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000252

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000171 AC: 26 AN: 151948 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74284

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.0000887 Hom.: 0

Bravo AF: 0.000453

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.000108 AC: 13

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2021

The c.2279C>A (p.A760E) alteration is located in exon 18 (coding exon 18) of the CSPP1 gene. This alteration results from a C to A substitution at nucleotide position 2279, causing the alanine (A) at amino acid position 760 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Joubert syndrome 21 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 13, 2022

This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 760 of the CSPP1 protein (p.Ala760Glu). This variant is present in population databases (rs376549634, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with CSPP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 474853). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	12
Dann	Benign	0.58
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.73	T;T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.012	T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	0.52	D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	2.5	N;N
REVEL	Benign	0.039
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0010	B;B
Vest4		0.36
MVP		0.16
MPC		0.15
ClinPred		0.020	T
GERP RS		1.8
gMVP		0.19

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

LitVar

Other links and lift over

dbSNP: rs376549634; hg19: chr8-68070734;