Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS1_Very_StrongPM1PM2PM5PP3_ModeratePP5_Moderate

The NM_174878.3(CLRN1):c.127G>C(p.Gly43Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G43V) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

CLRN1
NM_174878.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.37

Publications

0 publications found

Variant links:

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]

CLRN1 links:

ENSG00000243273 (HGNC:):

ENSG00000243273 links:

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

SIAH2-AS1 links:

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

CLRN1-AS1 links:

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ACMG classification

Classification was made for transcript

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

PS1

Transcript NM_174878.3 (CLRN1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_174878.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-150972581-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 802016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.91

PP5

Variant 3-150972582-C-G is Pathogenic according to our data. Variant chr3-150972582-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 2800316.Status of the report is criteria_provided_single_submitter, 1 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CLRN1	NM_174878.3	MANE Select	c.127G>C	p.Gly43Arg	missense	Exon 1 of 3	NP_777367.1
CLRN1	NM_001195794.1		c.127G>C	p.Gly43Arg	missense	Exon 1 of 4	NP_001182723.1
CLRN1	NM_001256819.2		c.127G>C	p.Gly43Arg	missense	Exon 1 of 4	NP_001243748.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CLRN1	ENST00000327047.6	TSL:1 MANE Select	c.127G>C	p.Gly43Arg	missense	Exon 1 of 3	ENSP00000322280.1
CLRN1	ENST00000328863.8	TSL:1	c.127G>C	p.Gly43Arg	missense	Exon 1 of 4	ENSP00000329158.4
CLRN1	ENST00000468836.2	TSL:3	c.103G>C	p.Gly35Arg	missense	Exon 1 of 4	ENSP00000419892.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.62

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.85

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.91

MetaSVM

Uncertain

0.060

MutationAssessor

Uncertain

2.3

PhyloP100

7.4

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.4

REVEL

Pathogenic

0.71

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.86

MutPred

0.79

Loss of sheet (P = 7e-04)

MVP

0.90

MPC

0.18

ClinPred

0.99

GERP RS

5.3

PromoterAI

0.0062

Neutral

(source)

Varity_R

0.60

gMVP

0.79

Mutation Taster

=31/69

disease causing

(source)

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

Publications

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rs111033434

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over