rs121908142

Positions:

• chr3-150928186-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_174878.3(CLRN1):​c.449T>C​(p.Leu150Pro) 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLRN1 NM_174878.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.17

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a chain Clarin-1 (size 231) in uniprot entity CLRN1_HUMAN there are 22 pathogenic changes around while only 1 benign (96%) in NM_174878.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949
• PP5: Variant 3-150928186-A-G is Pathogenic according to our data. Variant chr3-150928186-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4396.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-150928186-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLRN1	NM_174878.3	c.449T>C	p.Leu150Pro	missense_variant	3/3	ENST00000327047.6	NP_777367.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLRN1	ENST00000327047.6	c.449T>C	p.Leu150Pro	missense_variant	3/3	1	NM_174878.3	ENSP00000322280	P1
	ENST00000469268.1	n.235+37316A>G		intron_variant, non_coding_transcript_variant		4
CLRN1-AS1	ENST00000476886.5	n.123+75580A>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Usher syndrome type 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2002

- -

Retinitis pigmentosa 61 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	.;D;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	T;T;T
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Uncertain	2.3	.;M;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-5.6	D;D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.97
MutPred		0.77		.;Loss of stability (P = 0.0883);.;
MVP		0.93
MPC		0.20
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.94
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs121908142; hg19: chr3-150645973;