rs397515335

Positions:

chr1-243344276-AG-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_006642.5(SDCCAG8):c.1420delG(p.Glu474fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,934 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E474E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

SDCCAG8
NM_006642.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 3.29

Variant links:

Genes affected

SDCCAG8 (HGNC:10671): (SHH signaling and ciliogenesis regulator SDCCAG8) This gene encodes a centrosome associated protein. This protein may be involved in organizing the centrosome during interphase and mitosis. Mutations in this gene are associated with retinal-renal ciliopathy. [provided by RefSeq, Oct 2010]

SDCCAG8 links:

SDCCAG8 (HGNC:):

SDCCAG8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-243344276-AG-A is Pathogenic according to our data. Variant chr1-243344276-AG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 57.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-243344276-AG-A is described in Lovd as [Pathogenic]. Variant chr1-243344276-AG-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDCCAG8	NM_006642.5 linkuse as main transcript	c.1420delG	p.Glu474fs	frameshift_variant	12/18	ENST00000366541.8	NP_006633.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SDCCAG8	ENST00000366541.8 linkuse as main transcript	c.1420delG	p.Glu474fs	frameshift_variant	12/18	1	NM_006642.5	ENSP00000355499.3	Q86SQ7-1
SDCCAG8	ENST00000435549.1 linkuse as main transcript	c.760delG	p.Glu254fs	frameshift_variant	7/11	1		ENSP00000410200.1	A0A0C4DG71
SDCCAG8	ENST00000493334.1 linkuse as main transcript	n.387delG		non_coding_transcript_exon_variant	3/5	5

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251312

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135832

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461708

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727164

show subpopulations

Gnomad4 AFR exome

AF:

0.000388

Gnomad4 AMR exome

AF:

0.00

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:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.000314

Gnomad4 AMR

AF:

0.00

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:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000869

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Senior-Loken syndrome 7;C3889474:Bardet-Biedl syndrome 16

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2023	This premature translational stop signal has been observed in individual(s) with Senior-Loken syndrome (PMID: 20835237). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 57). This variant is present in population databases (rs770467138, gnomAD 0.02%). This sequence change creates a premature translational stop signal (p.Glu474Serfs*20) in the SDCCAG8 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SDCCAG8 are known to be pathogenic (PMID: 20835237, 22190896). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 04, 2021	- -

Bardet-Biedl syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 03, 2023	Variant summary: SDCCAG8 c.1420delG (p.Glu474SerfsX20) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.6e-05 in 251312 control chromosomes (gnomAD). c.1420delG has been reported in the literature in multiple individuals affected with nephronophthisis and retinal degeneration (Senior-Loken syndrome), including at least three homozygous individuals from two unrelated families (e.g. Otto_2010, Halbritter_2013, Al Alawi_2019). These data indicate that the variant is very likely to be associated with disease. Four submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=3)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 03, 2017	- -

Senior-Loken syndrome 7

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2010

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 24, 2019

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 22190896, 21866095, 20835237, 31844813) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over