1-243270236-G-T

Variant names:

• chr1-243270236-G-T
• rs756518004
• NM_006642.5:c.199G>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_006642.5(SDCCAG8):​c.199G>T​(p.Glu67*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000684 in 1,461,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SDCCAG8 NM_006642.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 5.47
• Publications: 1 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):

• Bardet-Biedl syndrome 16

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Genomics England PanelApp
• Senior-Loken syndrome 7

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• ciliopathy

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia
• 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 12 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 1-243270236-G-T is Pathogenic according to our data. Variant chr1-243270236-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 591885.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006642.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDCCAG8	NM_006642.5	MANE Select	c.199G>T	p.Glu67*	stop_gained	Exon 2 of 18	NP_006633.1	Q86SQ7-1
	SDCCAG8	NM_001350248.2		c.199G>T	p.Glu67*	stop_gained	Exon 2 of 19	NP_001337177.1
	SDCCAG8	NM_001350249.2		c.-96G>T		5_prime_UTR	Exon 2 of 18	NP_001337178.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDCCAG8	ENST00000366541.8	TSL:1 MANE Select	c.199G>T	p.Glu67*	stop_gained	Exon 2 of 18	ENSP00000355499.3	Q86SQ7-1
	SDCCAG8	ENST00000884080.1		c.199G>T	p.Glu67*	stop_gained	Exon 2 of 19	ENSP00000554139.1
	SDCCAG8	ENST00000951623.1		c.199G>T	p.Glu67*	stop_gained	Exon 2 of 18	ENSP00000621682.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461784 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727172

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111962

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (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	0.35
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Pathogenic	0.83
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.84	D
PhyloP100		5.5
Vest4		0.21
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=51/149	disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs756518004; hg19: chr1-243433538;