rs16846663

chr3-150940477-G-Achr3-150940477-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000328863.8(CLRN1):c.472+4C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0185 in 1,534,678 control chromosomes in the GnomAD database, including 2,490 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (330 hom., cov: 32)
  • Exomes 𝑓: 0.017 (2160 hom.)
• Consequence: CLRN1 ENST00000328863.8 splice_donor_region, intron
• Scores: Splicing: ADA: 0.004845
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.452

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 3-150940477-G-A is Benign according to our data. Variant chr3-150940477-G-A is described in ClinVar as [Benign]. Clinvar id is 226524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-150940477-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.304 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLRN1	NM_174878.3	c.433+1105C>T		intron_variant		ENST00000327047.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLRN1	ENST00000327047.6	c.433+1105C>T		intron_variant		1	NM_174878.3	P1
	ENST00000469268.1	n.235+49607G>A		intron_variant, non_coding_transcript_variant		4
CLRN1-AS1	ENST00000476886.5	n.123+87871G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0319 AC: 4854 AN: 152172 Hom.: 330 Cov.: 32

Gnomad AFR AF: 0.0370

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0413

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.318

Gnomad SAS AF: 0.0603

Gnomad FIN AF: 0.0343

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00459

Gnomad OTH AF: 0.0244

GnomAD3 exomes AF: 0.0492 AC: 6602 AN: 134086 Hom.: 663 AF XY: 0.0452 AC XY: 3302 AN XY: 73020

Gnomad AFR exome AF: 0.0405

Gnomad AMR exome AF: 0.0630

Gnomad ASJ exome AF: 0.00314

Gnomad EAS exome AF: 0.323

Gnomad SAS exome AF: 0.0390

Gnomad FIN exome AF: 0.0347

Gnomad NFE exome AF: 0.00383

Gnomad OTH exome AF: 0.0347

GnomAD4 exome AF: 0.0171 AC: 23576 AN: 1382388 Hom.: 2160 Cov.: 30 AF XY: 0.0174 AC XY: 11847 AN XY: 682154

Gnomad4 AFR exome AF: 0.0365

Gnomad4 AMR exome AF: 0.0595

Gnomad4 ASJ exome AF: 0.00326

Gnomad4 EAS exome AF: 0.310

Gnomad4 SAS exome AF: 0.0405

Gnomad4 FIN exome AF: 0.0339

Gnomad4 NFE exome AF: 0.00256

Gnomad4 OTH exome AF: 0.0342

GnomAD4 genome AF: 0.0319 AC: 4859 AN: 152290 Hom.: 330 Cov.: 32 AF XY: 0.0355 AC XY: 2646 AN XY: 74450

Gnomad4 AFR AF: 0.0370

Gnomad4 AMR AF: 0.0413

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.317

Gnomad4 SAS AF: 0.0605

Gnomad4 FIN AF: 0.0343

Gnomad4 NFE AF: 0.00459

Gnomad4 OTH AF: 0.0279

Alfa AF: 0.0113 Hom.: 17

Bravo AF: 0.0345

Asia WGS AF: 0.182 AC: 632 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 05, 2015	c.472+4C>T in intron 3 of CLRN1: This variant is not expected to have clinical s ignificance because it has been identified at high frequency in multiple populat ions, including in 3.7% (275/7400) of South Asian chromosomes by the Exome Aggre gation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs16846663). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 20, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 15, 2018	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, criteria provided, single submitter

clinical testing

Pars Genome Lab

Jun 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	1.3
Dann	Benign	0.40

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0048
dbscSNV1_RF	Benign	0.070
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: rs16846663; hg19: chr3-150658264;