chr1-243293111-G-A

Position:

• chr1-243293111-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_006642.5(SDCCAG8):​c.567G>A​(p.Trp189Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SDCCAG8 NM_006642.5 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 2.38

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]

ACMG classification

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 1-243293111-G-A is Pathogenic according to our data. Variant chr1-243293111-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 212141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDCCAG8	NM_006642.5	c.567G>A	p.Trp189Ter	stop_gained	6/18	ENST00000366541.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDCCAG8	ENST00000366541.8	c.567G>A	p.Trp189Ter	stop_gained	6/18	1	NM_006642.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

SDCCAG8-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 18, 2024

The SDCCAG8 c.567G>A variant is predicted to result in premature protein termination (p.Trp189*). To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. Nonsense variants in SDCCAG8 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Senior-Loken syndrome 7 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 17, 2015

- -

Senior-Loken syndrome 7;C3889474:Bardet-Biedl syndrome 16 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 06, 2022

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 212141). This variant has not been reported in the literature in individuals affected with SDCCAG8-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp189*) 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). -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 17, 2023

Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); Nonsense 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 -

Bardet-Biedl syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 21, 2021

Variant summary: SDCCAG8 c.567G>A (p.Trp189X) 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. Truncations downstream of this position have been reported in HGMD in association with Bardet-Biedl Syndrome. The variant was absent in 251464 control chromosomes. To our knowledge, no occurrence of c.567G>A in individuals affected with Bardet-Biedl Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	37
DANN	Uncertain	0.98
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.77	D
MutationTaster	Benign	1.0	A;A;A;D
Vest4		0.12
GERP RS		3.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: 11
DS_AL_spliceai		0.30		Position offset: -20

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

Publications

LitVar

Other links and lift over

dbSNP: rs797045948; hg19: chr1-243456413;