rs768318766

Variant names:

• chr1-243256053-C-T
• rs768318766
• NM_006642.5:c.-121C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_006642.5(SDCCAG8):​c.-121C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000465 in 914,336 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00050 (1 hom.)
• Consequence: SDCCAG8 NM_006642.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 1.90
• 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):

• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0005 (381/762114) while in subpopulation NFE AF = 0.000747 (355/475328). AF 95% confidence interval is 0.000683. There are 1 homozygotes in GnomAdExome4. There are 183 alleles in the male GnomAdExome4 subpopulation. Median coverage is 11. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDCCAG8	NM_006642.5	c.-121C>T		5_prime_UTR_variant	Exon 1 of 18	ENST00000366541.8	NP_006633.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDCCAG8	ENST00000366541.8	c.-121C>T		5_prime_UTR_variant	Exon 1 of 18	1	NM_006642.5	ENSP00000355499.3
SDCCAG8	ENST00000490065.5	n.20C>T		non_coding_transcript_exon_variant	Exon 1 of 5	4

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000500 AC: 381 AN: 762114 Hom.: 1 Cov.: 11 AF XY: 0.000451 AC XY: 183 AN XY: 405994

African (AFR) AF: 0.0000499 AC: 1 AN: 20034

American (AMR) AF: 0.0000230 AC: 1 AN: 43450

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21698

East Asian (EAS) AF: 0.00 AC: 0 AN: 36508

South Asian (SAS) AF: 0.00 AC: 0 AN: 72194

European-Finnish (FIN) AF: 0.000234 AC: 12 AN: 51280

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4230

European-Non Finnish (NFE) AF: 0.000747 AC: 355 AN: 475328

Other (OTH) AF: 0.000321 AC: 12 AN: 37392

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152222 Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18 AN XY: 74358

African (AFR) AF: 0.0000482 AC: 2 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000617 AC: 42 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000529 Hom.: 0

Bravo AF: 0.000329

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Senior-Loken syndrome 7 Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Bardet-Biedl syndrome 16 Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	18
DANN	Benign	0.88
PhyloP100		1.9
PromoterAI		0.12	Neutral
Mutation Taster		=298/2	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs768318766; hg19: chr1-243419355;