chr1-243305133-C-T

Variant names:

• chr1-243305133-C-T
• rs397515337
• NM_006642.5:c.740+356C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The NM_001350251.2(SDCCAG8):​c.-416C>T variant causes a 5 prime UTR premature start codon gain 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_001350251.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: -0.970

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 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 rank	MANE	Protein	UniProt
SDCCAG8	NM_006642.5	c.740+356C>T		intron_variant	Intron 7 of 17	ENST00000366541.8	NP_006633.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDCCAG8	ENST00000366541.8	c.740+356C>T		intron_variant	Intron 7 of 17	1	NM_006642.5	ENSP00000355499.3

Frequencies

GnomAD3 genomes AF: 0.0000658 AC: 10 AN: 151982 Hom.: 0 Cov.: 32

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: 1 AN: 8058 Hom.: 0 AF XY: 0.000217 AC XY: 1 AN XY: 4600

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: 8 AN: 65308 Hom.: 0 Cov.: 0 AF XY: 0.000109 AC XY: 4 AN XY: 36828

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: 10 AN: 151982 Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4 AN XY: 74232

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.: 0

Bravo AF: 0.0000718

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Senior-Loken syndrome 7 Pathogenic:2

Jun 01, 2018

Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Bardet-Biedl syndrome 16 Pathogenic:2

Sep 01, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 26, 2017

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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). -

SDCCAG8-related disorder Pathogenic:1

Sep 06, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. This variant is interpreted as likely pathogenic. -

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

Sep 30, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bardet-Biedl syndrome Pathogenic:1

May 17, 2022

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Other links and lift over

dbSNP: rs397515337; hg19: chr1-243468435;