rs397515337

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4

The NM_006642.5(SDCCAG8):c.740+356C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000828 in 217,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

SDCCAG8
NM_006642.5 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.970

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-243305133-C-T is Pathogenic according to our data. Variant chr1-243305133-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 60.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-243305133-C-T is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.01).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDCCAG8	NM_006642.5 linkuse as main transcript	c.740+356C>T		intron_variant		ENST00000366541.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDCCAG8	ENST00000366541.8 linkuse as main transcript	c.740+356C>T		intron_variant		1	NM_006642.5	P1	Q86SQ7-1

Frequencies

GnomAD3 genomes

AF:

0.0000658

AC:

AN:

151982

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000124

AC:

AN:

8058

Hom.:

AF XY:

0.000217

AC XY:

AN XY:

4600

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000300

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000122

AC:

AN:

65308

Hom.:

Cov.:

AF XY:

0.000109

AC XY:

AN XY:

36828

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.000173

Gnomad4 OTH exome

AF:

0.000320

GnomAD4 genome

AF:

0.0000658

AC:

AN:

151982

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74232

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000693

Hom.:

Bravo

AF:

0.0000718

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Bardet-Biedl syndrome 16

Pathogenic:2

Pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jun 26, 2017	PVS1: This is an intronic variant in most transcripts but there is functional evidence in the literature that it results in altered splicing and significantly reduced protein levels (PMID: 20835237). It is annotated as a missense here but that only applies to 1 transcript. PP1 it cosegregates in 1 large Gypsy family with 5 affected individuals in 2 sibships (PMID: 22190896). PM2 rare in population databases (AC = 2 in gnomAD). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2011	- -

SDCCAG8-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 27, 2022

The SDCCAG8 c.740+356C>T variant is predicted to interfere with splicing. This variant has been reported in the homozygous state in 5 affected individuals from two related Roma families with Bardet-Biedl syndrome (BBS) (Otto et al. 2010. PubMed ID: 20835237; Schaefer et al. 2011. PubMed ID: 22190896). Although this family was diagnosed with BBS, they were initially recruited due to acute manifestation of chronic renal failure coupled with respiratory defects. This deep intronic variant was predicted to disrupt an exonic splicing enhancer which was confirmed by cDNA sequencing (Otto et al. 2010. PubMed ID: 20835237). This variant was also described in the compound heterozygous state in an individual with Senior-Loken syndrome (Tay and Vincent. 2020. PubMed ID: 32432520) and in the homozygous state in an individual with suspected retinal disease (Weisschuh et al. 2020. PubMed ID: 32531858, supplementary data). Lastly, this variant was detected, along with a second causative variant, in another individual with Bardet-Biedl syndrome (Meyer et al. 2022. PubMed ID: 35112343). This variant is reported in 0.016% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-243468435-C-T). This variant is interpreted as likely pathogenic. -

Senior-Loken syndrome 7

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota

Jun 01, 2018

- -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 30, 2021

- -

Bardet-Biedl syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

May 17, 2022

Variant summary: SDCCAG8 c.740+356C>T is located at a position not widely known to affect splicing. 4/4 computational tools predict no significant impact on normal splicing. However, at least one publication reports experimental evidence that this variant affects mRNA splicing. The variant allele was found at a frequency of 0.00012 in 8058 control chromosomes. c.740+356C>T has been reported in the literature in multiple individuals affected with retinal-renal ciliopathy. These data indicate that the variant is very likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

Cadd

Benign

3.7

Dann

Benign

0.69

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