chr1-243270994-T-A

Position:

chr1-243270994-T-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D79Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00040 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00079 ( 0 hom. )

Consequence

SDCCAG8
NM_006642.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 0.702

Variant links:

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 links:

SDCCAG8 (HGNC:):

SDCCAG8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
SDCCAG8	NM_006642.5 linkuse as main transcript	c.237T>A	p.Asp79Glu	missense_variant	3/18	ENST00000366541.8	NP_006633.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SDCCAG8	ENST00000366541.8 linkuse as main transcript	c.237T>A	p.Asp79Glu	missense_variant	3/18	1	NM_006642.5	ENSP00000355499.3	Q86SQ7-1
SDCCAG8	ENST00000490065.5 linkuse as main transcript	n.390T>A		non_coding_transcript_exon_variant	3/5	4
SDCCAG8	ENST00000491888.1 linkuse as main transcript	n.248T>A		non_coding_transcript_exon_variant	3/3	3
SDCCAG8	ENST00000482234.1 linkuse as main transcript	n.-31T>A		upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000401

AC:

AN:

152086

Hom.:

Cov.:

show subpopulations

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:

AN:

251396

Hom.:

AF XY:

0.000397

AC XY:

AN XY:

135874

show subpopulations

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.:

Cov.:

AF XY:

0.000758

AC XY:

551

AN XY:

726952

show subpopulations

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:

AN:

152204

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74394

show subpopulations

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.:

Bravo

AF:

0.000374

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000329

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000771

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 05, 2024	- -

SDCCAG8-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 05, 2024

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 (Supplementary Table 5, Halbritter et al. 2012. PubMed ID: 23188109). 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 (Supplementary Data, Nasser et al. 2022. PubMed ID: 35886001). 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. -

Bardet-Biedl syndrome 16

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.011

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.69

M_CAP

Benign

0.0092

MetaRNN

Benign

0.019

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PrimateAI

Benign

0.32

PROVEAN

Benign

0.27

REVEL

Benign

0.051

Sift

Benign

0.43

Sift4G

Benign

1.0

Polyphen

0.075

Vest4

0.15

MutPred

0.13

Gain of methylation at K78 (P = 0.0908);

MVP

0.47

MPC

0.046

ClinPred

0.027

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over