rs567709615

chr3-150940521-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Moderate PM2 PP3_Strong

The ENST00000328863.8(CLRN1):c.434-2A>T variant causes a splice acceptor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000824 in 1,534,600 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00084 (1 hom.)
• Consequence: CLRN1 ENST00000328863.8 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 0.118

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]

(HGNC:):

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

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.051490515 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.6, offset of 18, new splice context is: tgttgccctttggctgccAGcta. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLRN1	NM_174878.3	c.433+1061A>T		intron_variant		ENST00000327047.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLRN1	ENST00000327047.6	c.433+1061A>T		intron_variant		1	NM_174878.3	P1
	ENST00000469268.1	n.235+49651T>A		intron_variant, non_coding_transcript_variant		4
CLRN1-AS1	ENST00000476886.5	n.123+87915T>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.000657 AC: 100 AN: 152234 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00121

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000507 AC: 68 AN: 134166 Hom.: 0 AF XY: 0.000411 AC XY: 30 AN XY: 73078

Gnomad AFR exome AF: 0.000156

Gnomad AMR exome AF: 0.0000411

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.00121

Gnomad OTH exome AF: 0.000242

GnomAD4 exome AF: 0.000843 AC: 1165 AN: 1382366 Hom.: 1 Cov.: 30 AF XY: 0.000831 AC XY: 567 AN XY: 682132

Gnomad4 AFR exome AF: 0.000127

Gnomad4 AMR exome AF: 0.0000841

Gnomad4 ASJ exome AF: 0.0000796

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000590

Gnomad4 NFE exome AF: 0.00104

Gnomad4 OTH exome AF: 0.000640

GnomAD4 genome AF: 0.000657 AC: 100 AN: 152234 Hom.: 0 Cov.: 32 AF XY: 0.000565 AC XY: 42 AN XY: 74372

Gnomad4 AFR AF: 0.000338

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00121

Gnomad4 OTH AF: 0.00143

Alfa AF: 0.000753 Hom.: 0

Bravo AF: 0.000642

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00156 AC: 6

ExAC AF: 0.0000617 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Usher syndrome type 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Dec 15, 2016

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 07, 2018

The c.434-2A>T variant in CLRN1 has been previously identified by our laboratory in five individuals with hearing loss, but none of these individuals had a vari ant affecting the remaining copy of the CLRN1 gene. This variant has been identi fied in 0.12% (81/68182) of European chromosomes by the Genome Aggregation Datab ase (http://gnomad.broadinstitute.org/). This variant is located at the -2 splic e site position near exon 3 of an alternate transcript (NM_001195794.1) of the C LRN1 gene, and is predicted to impact splicing of this transcript. However, in a ll other transcripts of the gene, including the major transcript (NM_174878.2), the variant lies in an intronic region that is distant from the splice sites of exons expressed in those transcripts and is not predicted to impact their splici ng. While this alternate transcript (NM_001195794.1) is reportedly expressed in the retina (Vastinsalo 2011), to date, pathogenic variants have not been reporte d in exon 3 of this transcript in individuals with Usher syndrome. Therefore, it is not clear whether abnormal splicing affecting only the alternate transcript can cause disease. In summary, the clinical significance of this variant is unce rtain. ACMG/AMP Criteria applied: PP3, BS1_Supporting. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 12, 2016

The c.434-2A>T variant in the CLRN1 gene has been reported previously in an individual with Usher syndrome, however a second variant was not identified (Bonnet et al., 2016). This splice site variant destroys the canonical splice acceptor site in intron 2. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.434-2A>T variant was not observed with any significant frequency in the Exome Aggregation Consortium (ExAC) data set, indicating it is not a common benign variant. We interpret c.434-2A>T as a variant of uncertain significance. -

Hearing impairment Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center

Apr 12, 2021

PVS1_Strong, PM2_Supporting, BP4_Supporting -

Retinitis pigmentosa Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 16, 2019

This variant was classified as: Uncertain significance. The available evidence favors the benign nature of this variant, however the evidence is insufficent to prove its benign nature. The following ACMG criteria were applied in classifying this variant: PM2. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	20
Dann	Benign	0.91
Eigen	Benign	0.17
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.029	N
MutationTaster	Benign	1.0	N;N;N
GERP RS		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.76
SpliceAI score (max)		0.050		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: rs567709615; hg19: chr3-150658308;