rs118064970

Positions:

• chr1-243344267-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_006642.5(SDCCAG8):​c.1409A>G​(p.Glu470Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000316 in 1,614,052 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00070 (4 hom., cov: 33)
  • Exomes 𝑓: 0.00028 (2 hom.)
• Consequence: SDCCAG8 NM_006642.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 6.42

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0057199).
• BP6: Variant 1-243344267-A-G is Benign according to our data. Variant chr1-243344267-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 167664.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=1, Uncertain_significance=1}. Variant chr1-243344267-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000702 (107/152336) while in subpopulation EAS AF= 0.0106 (55/5194). AF 95% confidence interval is 0.00835. There are 4 homozygotes in gnomad4. There are 31 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDCCAG8	NM_006642.5	c.1409A>G	p.Glu470Gly	missense_variant	12/18	ENST00000366541.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDCCAG8	ENST00000366541.8	c.1409A>G	p.Glu470Gly	missense_variant	12/18	1	NM_006642.5	P1
SDCCAG8	ENST00000435549.1	c.749A>G	p.Glu250Gly	missense_variant	7/11	1
SDCCAG8	ENST00000493334.1	n.376A>G		non_coding_transcript_exon_variant	3/5	5

Frequencies

GnomAD3 genomes AF: 0.000690 AC: 105 AN: 152218 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0102

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000792 AC: 199 AN: 251270 Hom.: 2 AF XY: 0.000699 AC XY: 95 AN XY: 135812

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00952

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000276 AC: 403 AN: 1461716 Hom.: 2 Cov.: 31 AF XY: 0.000239 AC XY: 174 AN XY: 727156

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00537

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00282

GnomAD4 genome AF: 0.000702 AC: 107 AN: 152336 Hom.: 4 Cov.: 33 AF XY: 0.000416 AC XY: 31 AN XY: 74488

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.00189

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0106

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.000638 Hom.: 3

Bravo AF: 0.000759

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000708 AC: 86

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jan 20, 2014

- -

SDCCAG8-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 01, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Senior-Loken syndrome 7 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Bardet-Biedl syndrome 16 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.29	T;T
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.0057	T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.6	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Benign	0.27
Sift	Uncertain	0.027	D;D
Sift4G	Uncertain	0.012	D;T
Polyphen		1.0	D;.
Vest4		0.65
MVP		0.55
MPC		0.30
ClinPred		0.052	T
GERP RS		6.1
Varity_R		0.33
gMVP		0.21

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: rs118064970; hg19: chr1-243507569;