rs146474568

chr1-243270994-T-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_006642.5(SDCCAG8):c.237T>A(p.Asp79Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000751 in 1,613,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00079 (0 hom.)
• Consequence: SDCCAG8 NM_006642.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.702

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_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.018621087).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000788 (1151/1461154) while in subpopulation NFE AF= 0.000911 (1012/1111460). AF 95% confidence interval is 0.000863. There are 0 homozygotes in gnomad4_exome. There are 551 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDCCAG8	NM_006642.5	c.237T>A	p.Asp79Glu	missense_variant	3/18	ENST00000366541.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDCCAG8	ENST00000366541.8	c.237T>A	p.Asp79Glu	missense_variant	3/18	1	NM_006642.5	P1
SDCCAG8	ENST00000490065.5	n.390T>A		non_coding_transcript_exon_variant	3/5	4
SDCCAG8	ENST00000491888.1	n.248T>A		non_coding_transcript_exon_variant	3/3	3
SDCCAG8	ENST00000482234.1			upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152086 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000366 AC: 92 AN: 251396 Hom.: 0 AF XY: 0.000397 AC XY: 54 AN XY: 135874

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000719

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000519

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000788 AC: 1151 AN: 1461154 Hom.: 0 Cov.: 29 AF XY: 0.000758 AC XY: 551 AN XY: 726952

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000754

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000911

Gnomad4 OTH exome AF: 0.000944

GnomAD4 genome AF: 0.000401 AC: 61 AN: 152204 Hom.: 0 Cov.: 31 AF XY: 0.000336 AC XY: 25 AN XY: 74394

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000750

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000744 Hom.: 0

Bravo AF: 0.000374

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000329 AC: 40

EpiCase AF: 0.000382

EpiControl AF: 0.000771

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

SDCCAG8-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 05, 2023

The SDCCAG8 c.237T>A variant is predicted to result in the amino acid substitution p.Asp79Glu. This variant was reported in an individual with nephronophthisis-associated ciliopathies; however, a second SDCCAG8 variant was not identified (Halbritter et al. 2012. PubMed ID: 23188109, supplementary table 5). Additionally, this variant was identified as a variant of uncertain significance in a large cohort of individuals with retinal disorders (Dineiro et al. 2020. PubMed ID: 32483926). This variant was also described in a large cohort of individuals with Bardet-Biedl syndrome; however, this individual harbored a homozygous BBS9 deletion (Nasser et al. 2022. PubMed ID: 35886001, supplementary data). This variant is reported in 0.072% of alleles in individuals of South Asian descent in gnomAD, which is likely too common to be a primary cause of disease. Although we suspect this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Senior-Loken syndrome 7 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 27, 2023

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 79 of the SDCCAG8 protein (p.Asp79Glu). This variant is present in population databases (rs146474568, gnomAD 0.07%). This missense change has been observed in individual(s) with a nephronophthisis-associated ciliopathy and/or inherited retinal disorder (PMID: 23188109, 32483926). ClinVar contains an entry for this variant (Variation ID: 296904). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SDCCAG8 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Bardet-Biedl syndrome 16 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	19
Dann	Uncertain	0.98
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.69	D
M_CAP	Benign	0.0092	T
MetaRNN	Benign	0.019	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.27	N
REVEL	Benign	0.051
Sift	Benign	0.43	T
Sift4G	Benign	1.0	T
Polyphen		0.075	B
Vest4		0.15
MutPred		0.13		Gain of methylation at K78 (P = 0.0908);
MVP		0.47
MPC		0.046
ClinPred		0.027	T
GERP RS		0.14
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.021
gMVP		0.072

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs146474568; hg19: chr1-243434296;