chr1-243293111-G-A

Variant names:

• chr1-243293111-G-A
• rs797045948
• NM_006642.5:c.567G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001350248.2(SDCCAG8):​c.567G>A​(p.Trp189*) 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_001350248.2 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 2.38
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Senior-Loken syndrome 7

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• Bardet-Biedl syndrome 16

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• Bardet-Biedl syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Senior-Loken syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 212141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001350248.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDCCAG8	NM_006642.5	MANE Select	c.567G>A	p.Trp189*	stop_gained	Exon 6 of 18	NP_006633.1
	SDCCAG8	NM_001350248.2		c.567G>A	p.Trp189*	stop_gained	Exon 6 of 19	NP_001337177.1
	SDCCAG8	NM_001350249.2		c.273G>A	p.Trp91*	stop_gained	Exon 6 of 18	NP_001337178.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDCCAG8	ENST00000366541.8	TSL:1 MANE Select	c.567G>A	p.Trp189*	stop_gained	Exon 6 of 18	ENSP00000355499.3
	SDCCAG8	ENST00000435549.1	TSL:1	c.15+6714G>A		intron	N/A	ENSP00000410200.1
	SDCCAG8	ENST00000884080.1		c.567G>A	p.Trp189*	stop_gained	Exon 6 of 19	ENSP00000554139.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Bardet-Biedl syndrome (1)
1	-	-	not provided (1)
1	-	-	SDCCAG8-related disorder (1)
1	-	-	Senior-Loken syndrome 7 (1)
1	-	-	Senior-Loken syndrome 7;C3889474:Bardet-Biedl syndrome 16 (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		2.4
Vest4		0.12
GERP RS		3.2
Mutation Taster		=10/190	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs797045948; hg19: chr1-243456413;