rs6443206

Variant names:

• chr3-8778389-A-G
• rs6443206
• ENST00000427329.5:c.294-2725T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000427329.5(RAD18):​c.294-2725T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.347 in 152,102 control chromosomes in the GnomAD database, including 12,938 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.35 (12938 hom., cov: 32)
• Consequence: RAD18 ENST00000427329.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.326
• Publications: 10 publications found

Genes affected

RAD18 (HGNC:18278): (RAD18 E3 ubiquitin protein ligase) The protein encoded by this gene is highly similar to S. cerevisiae DNA damage repair protein Rad18. Yeast Rad18 functions through its interaction with Rad6, which is an ubiquitin-conjugating enzyme required for post-replication repair of damaged DNA. Similar to its yeast counterpart, this protein is able to interact with the human homolog of yeast Rad6 protein through a conserved ring-finger motif. Mutation of this motif results in defective replication of UV-damaged DNA and hypersensitivity to multiple mutagens. [provided by RefSeq, Jul 2008]

CAV3 (HGNC:1529): (caveolin 3) This gene encodes a caveolin family member, which functions as a component of the caveolae plasma membranes found in most cell types. Caveolin proteins are proposed to be scaffolding proteins for organizing and concentrating certain caveolin-interacting molecules. Mutations identified in this gene lead to interference with protein oligomerization or intra-cellular routing, disrupting caveolae formation and resulting in Limb-Girdle muscular dystrophy type-1C (LGMD-1C), hyperCKemia or rippling muscle disease (RMD). Alternative splicing has been identified for this locus, with inclusion or exclusion of a differentially spliced intron. In addition, transcripts utilize multiple polyA sites and contain two potential translation initiation sites. [provided by RefSeq, Jul 2008]

CAV3 Gene-Disease associations (from GenCC):

• caveolinopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal dominant limb-girdle muscular dystrophy type 1C

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• long QT syndrome 9

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• rippling muscle disease 2

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• distal myopathy, Tateyama type

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• inherited rippling muscle disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Brugada syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp
• hypertrophic cardiomyopathy 1

  Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia
• long QT syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.691 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD18	ENST00000427329.5	c.294-2725T>C		intron_variant	Intron 3 of 3	3		ENSP00000412054.1
CAV3	ENST00000472766.1	n.215+853A>G		intron_variant	Intron 2 of 2	2

Frequencies

GnomAD3 genomes AF: 0.347 AC: 52717 AN: 151984 Hom.: 12883 Cov.: 32

Gnomad AFR AF: 0.697

Gnomad AMI AF: 0.151

Gnomad AMR AF: 0.221

Gnomad ASJ AF: 0.182

Gnomad EAS AF: 0.0745

Gnomad SAS AF: 0.204

Gnomad FIN AF: 0.224

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.225

Gnomad OTH AF: 0.304

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.347 AC: 52836 AN: 152102 Hom.: 12938 Cov.: 32 AF XY: 0.340 AC XY: 25306 AN XY: 74348

African (AFR) AF: 0.698 AC: 28923 AN: 41448

American (AMR) AF: 0.221 AC: 3370 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.182 AC: 630 AN: 3468

East Asian (EAS) AF: 0.0744 AC: 385 AN: 5172

South Asian (SAS) AF: 0.205 AC: 992 AN: 4832

European-Finnish (FIN) AF: 0.224 AC: 2376 AN: 10590

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.225 AC: 15308 AN: 68000

Other (OTH) AF: 0.311 AC: 654 AN: 2106

Alfa AF: 0.263 Hom.: 7261

Bravo AF: 0.361

Asia WGS AF: 0.199 AC: 692 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	4.7
DANN	Benign	0.83
PhyloP100		0.33

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs6443206; hg19: chr3-8820075;