1-243330605-A-T

Variant names:

• chr1-243330605-A-T
• rs2275155
• NM_006642.5:c.1134A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006642.5(SDCCAG8):​c.1134A>T​(p.Glu378Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.3 in 1,613,592 control chromosomes in the GnomAD database, including 75,398 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5461 hom., cov: 32)
  • Exomes 𝑓: 0.30 (69937 hom.)
• Consequence: SDCCAG8 NM_006642.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.125
• Publications: 39 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00143978).
• BP6: Variant 1-243330605-A-T is Benign according to our data. Variant chr1-243330605-A-T is described in ClinVar as Benign. ClinVar VariationId is 260006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.439 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006642.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDCCAG8	NM_006642.5	MANE Select	c.1134A>T	p.Glu378Asp	missense	Exon 10 of 18	NP_006633.1
	SDCCAG8	NM_001350248.2		c.1230A>T	p.Glu410Asp	missense	Exon 11 of 19	NP_001337177.1
	SDCCAG8	NM_001350249.2		c.840A>T	p.Glu280Asp	missense	Exon 10 of 18	NP_001337178.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDCCAG8	ENST00000366541.8	TSL:1 MANE Select	c.1134A>T	p.Glu378Asp	missense	Exon 10 of 18	ENSP00000355499.3
	SDCCAG8	ENST00000435549.1	TSL:1	c.474A>T	p.Glu158Asp	missense	Exon 5 of 11	ENSP00000410200.1

Frequencies

GnomAD3 genomes AF: 0.262 AC: 39858 AN: 151898 Hom.: 5463 Cov.: 32

Gnomad AFR AF: 0.194

Gnomad AMI AF: 0.308

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.350

Gnomad EAS AF: 0.186

Gnomad SAS AF: 0.455

Gnomad FIN AF: 0.276

Gnomad MID AF: 0.350

Gnomad NFE AF: 0.299

Gnomad OTH AF: 0.265

GnomAD2 exomes AF: 0.294 AC: 73899 AN: 251280 AF XY: 0.308

Gnomad AFR exome AF: 0.195

Gnomad AMR exome AF: 0.192

Gnomad ASJ exome AF: 0.362

Gnomad EAS exome AF: 0.196

Gnomad FIN exome AF: 0.282

Gnomad NFE exome AF: 0.306

Gnomad OTH exome AF: 0.304

GnomAD4 exome AF: 0.304 AC: 444396 AN: 1461576 Hom.: 69937 Cov.: 35 AF XY: 0.311 AC XY: 225884 AN XY: 727104

African (AFR) AF: 0.193 AC: 6447 AN: 33476

American (AMR) AF: 0.199 AC: 8891 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.353 AC: 9218 AN: 26126

East Asian (EAS) AF: 0.188 AC: 7450 AN: 39692

South Asian (SAS) AF: 0.454 AC: 39180 AN: 86254

European-Finnish (FIN) AF: 0.286 AC: 15278 AN: 53416

Middle Eastern (MID) AF: 0.380 AC: 2192 AN: 5768

European-Non Finnish (NFE) AF: 0.304 AC: 337621 AN: 1111740

Other (OTH) AF: 0.300 AC: 18119 AN: 60380

GnomAD4 genome AF: 0.262 AC: 39851 AN: 152016 Hom.: 5461 Cov.: 32 AF XY: 0.264 AC XY: 19650 AN XY: 74292

African (AFR) AF: 0.194 AC: 8035 AN: 41452

American (AMR) AF: 0.214 AC: 3275 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.350 AC: 1215 AN: 3472

East Asian (EAS) AF: 0.186 AC: 962 AN: 5172

South Asian (SAS) AF: 0.455 AC: 2187 AN: 4810

European-Finnish (FIN) AF: 0.276 AC: 2911 AN: 10546

Middle Eastern (MID) AF: 0.342 AC: 100 AN: 292

European-Non Finnish (NFE) AF: 0.299 AC: 20330 AN: 67970

Other (OTH) AF: 0.264 AC: 556 AN: 2108

Alfa AF: 0.268 Hom.: 1789

Bravo AF: 0.252

TwinsUK AF: 0.307 AC: 1138

ALSPAC AF: 0.304 AC: 1172

ESP6500AA AF: 0.191 AC: 843

ESP6500EA AF: 0.308 AC: 2645

ExAC AF: 0.297 AC: 36107

Asia WGS AF: 0.322 AC: 1121 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

May 26, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Senior-Loken syndrome 7 Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

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

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Bardet-Biedl syndrome 16 Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

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

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.13
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.16
Sift	Benign	0.14	T
Sift4G	Benign	0.089	T
Polyphen		0.12	B
Vest4		0.17
MutPred		0.023		Gain of MoRF binding (P = 0.0851)
MPC		0.052
ClinPred		0.016	T
GERP RS		0.25
Varity_R		0.13
gMVP		0.16
Mutation Taster		=89/11	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2275155; hg19: chr1-243493907; COSMIC: COSV59405589;