rs786204428

Variant names:

• chr3-150972557-CCTG-ATTGGACA
• rs786204428
• NM_174878.3:c.149_152delCAGGinsTGTCCAAT

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_174878.3(CLRN1):​c.149_152delCAGGinsTGTCCAAT​(p.Ser50LeufsTer12) variant causes a frameshift, missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CLRN1 NM_174878.3 frameshift, missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 7.40
• Publications: 5 publications found

Genes affected

CLRN1 (HGNC:12605): (clarin 1) This gene encodes a protein that contains a cytosolic N-terminus, multiple helical transmembrane domains, and an endoplasmic reticulum membrane retention signal, TKGH, in the C-terminus. The encoded protein may be important in development and homeostasis of the inner ear and retina. Mutations within this gene have been associated with Usher syndrome type IIIa. Multiple transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

ENSG00000243273 (HGNC:):

SIAH2-AS1 (HGNC:40526): (SIAH2 antisense RNA 1)

CLRN1-AS1 (HGNC:30895): (CLRN1 antisense RNA 1)

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-150972557-CCTG-ATTGGACA is Pathogenic according to our data. Variant chr3-150972557-CCTG-ATTGGACA is described in ClinVar as Pathogenic. ClinVar VariationId is 188726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_174878.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLRN1	NM_174878.3	MANE Select	c.149_152delCAGGinsTGTCCAAT	p.Ser50LeufsTer12	frameshift missense	Exon 1 of 3	NP_777367.1	P58418-3
	CLRN1	NM_001195794.1		c.149_152delCAGGinsTGTCCAAT	p.Ser50LeufsTer12	frameshift missense	Exon 1 of 4	NP_001182723.1	P58418-4
	CLRN1	NM_001256819.2		c.149_152delCAGGinsTGTCCAAT	p.Ser50LeufsTer12	frameshift missense	Exon 1 of 4	NP_001243748.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLRN1	ENST00000327047.6	TSL:1 MANE Select	c.149_152delCAGGinsTGTCCAAT	p.Ser50LeufsTer12	frameshift missense	Exon 1 of 3	ENSP00000322280.1	P58418-3
	CLRN1	ENST00000328863.8	TSL:1	c.149_152delCAGGinsTGTCCAAT	p.Ser50LeufsTer12	frameshift missense	Exon 1 of 4	ENSP00000329158.4	P58418-4
	CLRN1	ENST00000468836.2	TSL:3	c.125_128delCAGGinsTGTCCAAT	p.Ser42LeufsTer12	frameshift missense	Exon 1 of 4	ENSP00000419892.2	C9JYI2

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)
3	-	-	Usher syndrome type 3 (3)
1	-	-	Rare genetic deafness (1)
1	-	-	Retinal dystrophy (1)
1	-	-	Retinitis pigmentosa 61 (1)
1	-	-	Retinitis pigmentosa 61;C5779850:Usher syndrome type 3A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.4
Mutation Taster		=1/199	disease causing (fs/PTC)

Splicing

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

Other links and lift over

dbSNP: rs786204428; hg19: chr3-150690344;