chr1-243271024-T-C

Position:

• chr1-243271024-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_006642.5(SDCCAG8):​c.267T>C​(p.Ser89=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000943 in 1,613,524 control chromosomes in the GnomAD database, including 2 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 0.00065 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00097 (2 hom.)
• Consequence: SDCCAG8 NM_006642.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 1.60

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 1-243271024-T-C is Benign according to our data. Variant chr1-243271024-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 167663.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=3, Benign=1}. Variant chr1-243271024-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.6 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000974 (1423/1461402) while in subpopulation NFE AF= 0.00111 (1234/1111676). AF 95% confidence interval is 0.00106. There are 2 homozygotes in gnomad4_exome. There are 688 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDCCAG8	NM_006642.5	c.267T>C	p.Ser89=	synonymous_variant	3/18	ENST00000366541.8	NP_006633.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDCCAG8	ENST00000366541.8	c.267T>C	p.Ser89=	synonymous_variant	3/18	1	NM_006642.5	ENSP00000355499	P1
SDCCAG8	ENST00000490065.5	n.420T>C		non_coding_transcript_exon_variant	3/5	4
SDCCAG8	ENST00000491888.1	n.278T>C		non_coding_transcript_exon_variant	3/3	3
SDCCAG8	ENST00000482234.1			upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.000651 AC: 99 AN: 152122 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000985

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000823 AC: 207 AN: 251390 Hom.: 1 AF XY: 0.000817 AC XY: 111 AN XY: 135860

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.00437

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00111

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000974 AC: 1423 AN: 1461402 Hom.: 2 Cov.: 29 AF XY: 0.000946 AC XY: 688 AN XY: 727038

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000827

Gnomad4 ASJ exome AF: 0.00387

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.00111

Gnomad4 OTH exome AF: 0.000729

GnomAD4 genome AF: 0.000651 AC: 99 AN: 152122 Hom.: 0 Cov.: 31 AF XY: 0.000498 AC XY: 37 AN XY: 74312

Gnomad4 AFR AF: 0.000314

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000985

Gnomad4 OTH AF: 0.000955

Alfa AF: 0.00109 Hom.: 0

Bravo AF: 0.000752

EpiCase AF: 0.000981

EpiControl AF: 0.00166

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Mar 19, 2014

- -

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. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 02, 2016

- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 22, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	9.7
DANN	Benign	0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs148818431; hg19: chr1-243434326;