rs111033422

Positions:

• chr3-150972703-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_174878.3(CLRN1):​c.6A>C​(p.Pro2=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0086 in 1,614,180 control chromosomes in the GnomAD database, including 665 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (318 hom., cov: 33)
  • Exomes 𝑓: 0.0057 (347 hom.)
• Consequence: CLRN1 NM_174878.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 0.309

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

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 3-150972703-T-G is Benign according to our data. Variant chr3-150972703-T-G is described in ClinVar as [Benign]. Clinvar id is 48148.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-150972703-T-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.309 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.121 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLRN1	NM_174878.3	c.6A>C	p.Pro2=	synonymous_variant	1/3	ENST00000327047.6	NP_777367.1
CLRN1-AS1	NR_024066.2	n.26T>G		non_coding_transcript_exon_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLRN1	ENST00000327047.6	c.6A>C	p.Pro2=	synonymous_variant	1/3	1	NM_174878.3	ENSP00000322280	P1
	ENST00000469268.1	n.236-28871T>G		intron_variant, non_coding_transcript_variant		4
CLRN1-AS1	ENST00000476886.5	n.124-90223T>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0363 AC: 5521 AN: 152172 Hom.: 314 Cov.: 33

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0331

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.0230

GnomAD3 exomes AF: 0.0132 AC: 3318 AN: 251066 Hom.: 133 AF XY: 0.0120 AC XY: 1635 AN XY: 135718

Gnomad AFR exome AF: 0.128

Gnomad AMR exome AF: 0.00601

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0301

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000494

Gnomad OTH exome AF: 0.00685

GnomAD4 exome AF: 0.00570 AC: 8328 AN: 1461890 Hom.: 347 Cov.: 32 AF XY: 0.00606 AC XY: 4410 AN XY: 727246

Gnomad4 AFR exome AF: 0.129

Gnomad4 AMR exome AF: 0.00631

Gnomad4 ASJ exome AF: 0.00145

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0292

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000388

Gnomad4 OTH exome AF: 0.0112

GnomAD4 genome AF: 0.0365 AC: 5559 AN: 152290 Hom.: 318 Cov.: 33 AF XY: 0.0359 AC XY: 2673 AN XY: 74482

Gnomad4 AFR AF: 0.124

Gnomad4 AMR AF: 0.0107

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0329

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000588

Gnomad4 OTH AF: 0.0227

Alfa AF: 0.00682 Hom.: 77

Bravo AF: 0.0407

Asia WGS AF: 0.0270 AC: 92 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.00101

ClinVar

Significance: Benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

not provided, no classification provided	literature only	NEI Ophthalmic Genomics Laboratory, National Institutes of Health	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Usher syndrome type 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Counsyl	Jan 19, 2018	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 09, 2011	Pro2Pro in exon 1 of CLRN1: This variant is predicted to be benign based on its high frequency in the general population (dbSNP rs111033422). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 30, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Usher syndrome type 3A Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	9.5
DANN	Benign	0.74

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

Other links and lift over

dbSNP: rs111033422; hg19: chr3-150690490;