rs187218889

Positions:

chr3-150972700-G-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1BP4_StrongBP6BS2

The NM_174878.3(CLRN1):c.9C>A(p.Ser3Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000254 in 1,614,218 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00025 ( 2 hom. )

Consequence

CLRN1
NM_174878.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 2.55

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:

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

CLRN1-AS1 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 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

BP4

Computational evidence support a benign effect (MetaRNN=0.005288601).

BP6

Variant 3-150972700-G-T is Benign according to our data. Variant chr3-150972700-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48149.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=2, Uncertain_significance=2}.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLRN1	NM_174878.3 linkuse as main transcript	c.9C>A	p.Ser3Arg	missense_variant	1/3	ENST00000327047.6	NP_777367.1
CLRN1-AS1	NR_024066.2 linkuse as main transcript	n.23G>T		non_coding_transcript_exon_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLRN1	ENST00000327047.6 linkuse as main transcript	c.9C>A	p.Ser3Arg	missense_variant	1/3	1	NM_174878.3	ENSP00000322280	P1	P58418-3
	ENST00000469268.1 linkuse as main transcript	n.236-28874G>T		intron_variant, non_coding_transcript_variant		4
CLRN1-AS1	ENST00000476886.5 linkuse as main transcript	n.124-90226G>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.000282

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00712

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000617

AC:

155

AN:

251058

Hom.:

AF XY:

0.000619

AC XY:

AN XY:

135712

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000695

Gnomad EAS exome

AF:

0.00772

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000251

AC:

367

AN:

1461886

Hom.:

Cov.:

AF XY:

0.000257

AC XY:

187

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000612

Gnomad4 EAS exome

AF:

0.00778

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.000414

GnomAD4 genome

AF:

0.000282

AC:

AN:

152332

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00713

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000286

Hom.:

Bravo

AF:

0.000385

ExAC

AF:

0.000634

AC:

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 27, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 08, 2016	- -

Retinal dystrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 18, 2016

p.Ser3Arg in exon 1 of CLRN1: This variant is not expected to have clinical sign ificance because it has been identified in 0.8% (73/8624) of East Asian chromoso mes Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP s1 87218889). -

Usher syndrome type 3A

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Dec 13, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.37

T;.

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.43

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.77

T;T

M_CAP

Benign

0.043

MetaRNN

Benign

0.0053

T;T

MetaSVM

Benign

-0.63

MutationAssessor

Benign

1.8

L;L

MutationTaster

Benign

0.62

D;N

PrimateAI

Benign

0.30

PROVEAN

Uncertain

-2.5

N;D

REVEL

Benign

0.17

Sift

Uncertain

0.010

D;D

Sift4G

Uncertain

0.050

T;D

Polyphen

0.047

B;.

Vest4

0.14

MutPred

0.20

Loss of glycosylation at P2 (P = 0.0057);Loss of glycosylation at P2 (P = 0.0057);

MVP

0.75

MPC

0.027

ClinPred

0.047

GERP RS

3.6

Varity_R

0.16

gMVP

0.44

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over