dbSNP rs374390376: CLRN1:p.Pro31Leu (chr3-150972617-G-A) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_174878.3(CLRN1):c.92C>T(p.Pro31Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P31R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

CLRN1
NM_174878.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 2.93

Publications

7 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 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-150972617-G-A is Pathogenic according to our data. Variant chr3-150972617-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 30575.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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CLRN1	NM_174878.3	MANE Select	c.92C>T	p.Pro31Leu	missense	Exon 1 of 3	NP_777367.1	P58418-3
CLRN1	NM_001195794.1		c.92C>T	p.Pro31Leu	missense	Exon 1 of 4	NP_001182723.1	P58418-4
CLRN1	NM_001256819.2		c.92C>T	p.Pro31Leu	missense	Exon 1 of 4	NP_001243748.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CLRN1	ENST00000327047.6	TSL:1 MANE Select	c.92C>T	p.Pro31Leu	missense	Exon 1 of 3	ENSP00000322280.1	P58418-3
CLRN1	ENST00000328863.8	TSL:1	c.92C>T	p.Pro31Leu	missense	Exon 1 of 4	ENSP00000329158.4	P58418-4
CLRN1	ENST00000468836.2	TSL:3	c.68C>T	p.Pro23Leu	missense	Exon 1 of 4	ENSP00000419892.2	C9JYI2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Retinal dystrophy (1)

Retinitis pigmentosa 61 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.56

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.88

M_CAP

Uncertain

0.099

MetaRNN

Uncertain

0.72

MetaSVM

Benign

-0.36

MutationAssessor

Benign

1.4

PhyloP100

2.9

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-3.2

REVEL

Uncertain

0.51

Sift

Uncertain

0.0060

Sift4G

Benign

0.10

Polyphen

0.99

Vest4

0.43

MutPred

0.55

Gain of catalytic residue at P31 (P = 0.0055)

MVP

0.88

MPC

0.14

ClinPred

0.99

GERP RS

4.4

PromoterAI

0.0062

Neutral

(source)

Varity_R

0.19

gMVP

0.58

Mutation Taster

=10/90

disease causing (ClinVar)

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over