8-67149929-A-G

Variant names:

• chr8-67149929-A-G
• rs201316149
• NM_001382391.1:c.2122A>G

Variant summary

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

The NM_001382391.1(CSPP1):​c.2122A>G​(p.Ser708Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000418 in 1,557,668 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S708R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00032 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (8 hom.)
• Consequence: CSPP1 NM_001382391.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.87
• Publications: 4 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, G2P, Labcorp Genetics (formerly Invitae)
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0044882894).
• BP6: Variant 8-67149929-A-G is Benign according to our data. Variant chr8-67149929-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 541697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000319 (48/150602) while in subpopulation SAS AF = 0.00987 (47/4764). AF 95% confidence interval is 0.00762. There are 2 homozygotes in GnomAd4. There are 31 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSPP1	NM_001382391.1	MANE Select	c.2122A>G	p.Ser708Gly	missense	Exon 18 of 31	NP_001369320.1	A0A7I2V5W3
	CSPP1	NM_001364869.1		c.2188A>G	p.Ser730Gly	missense	Exon 17 of 30	NP_001351798.1	A0A7I2PHE7
	CSPP1	NM_024790.7		c.2107A>G	p.Ser703Gly	missense	Exon 16 of 29	NP_079066.5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSPP1	ENST00000678616.1	MANE Select	c.2122A>G	p.Ser708Gly	missense	Exon 18 of 31	ENSP00000504733.1	A0A7I2V5W3
	CSPP1	ENST00000262210.11	TSL:1	c.2188A>G	p.Ser730Gly	missense	Exon 17 of 30	ENSP00000262210.6	A0A7I2PHE7
	CSPP1	ENST00000519668.1	TSL:1	c.1079-4095A>G		intron	N/A	ENSP00000430092.1	Q1MSJ5-2

Frequencies

GnomAD3 genomes AF: 0.000326 AC: 49 AN: 150494 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0101

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00101 AC: 196 AN: 193808 AF XY: 0.00119

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000954

GnomAD4 exome AF: 0.000429 AC: 603 AN: 1407066 Hom.: 8 Cov.: 32 AF XY: 0.000595 AC XY: 416 AN XY: 699284

African (AFR) AF: 0.0000332 AC: 1 AN: 30076

American (AMR) AF: 0.00 AC: 0 AN: 29662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23346

East Asian (EAS) AF: 0.00 AC: 0 AN: 38424

South Asian (SAS) AF: 0.00732 AC: 556 AN: 75960

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51736

Middle Eastern (MID) AF: 0.000364 AC: 2 AN: 5496

European-Non Finnish (NFE) AF: 0.00000183 AC: 2 AN: 1094624

Other (OTH) AF: 0.000727 AC: 42 AN: 57742

GnomAD4 genome AF: 0.000319 AC: 48 AN: 150602 Hom.: 2 Cov.: 32 AF XY: 0.000422 AC XY: 31 AN XY: 73496

African (AFR) AF: 0.0000243 AC: 1 AN: 41090

American (AMR) AF: 0.00 AC: 0 AN: 14902

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5112

South Asian (SAS) AF: 0.00987 AC: 47 AN: 4764

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10156

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67834

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.000102 Hom.: 0

Bravo AF: 0.0000680

ExAC AF: 0.00115 AC: 139

Asia WGS AF: 0.00202 AC: 7 AN: 3472

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Joubert syndrome 21 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	22
DANN	Benign	0.97
Eigen	Benign	-0.12
Eigen_PC	Benign	0.14
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-1.1	T
PhyloP100		6.9
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.027
Sift	Benign	0.50	T
Sift4G	Benign	0.37	T
Polyphen		0.0010	B
Vest4		0.34
MVP		0.29
MPC		0.11
ClinPred		0.080	T
GERP RS		6.0
gMVP		0.21
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs201316149; hg19: chr8-68062164;