Genetic Variant CLRN1:c.433+1105C>T (chr3-150940477-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001195794.1(CLRN1):c.472+4C>T variant causes a splice 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. 3/3 splice prediction tools predict no significant impact on normal splicing. 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
NM_001195794.1 splice_region, intron

Scores

Splicing: ADA: 0.004845

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.452

Publications

8 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:

ENSG00000260234 (HGNC:):

ENSG00000260234 links:

SIAH2-AS1 (HGNC:40526): (SIAH2 antisense RNA 1)

SIAH2-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 226524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.304 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001195794.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CLRN1	NM_174878.3	MANE Select	c.433+1105C>T	intron	N/A	NP_777367.1	P58418-3
CLRN1	NM_001195794.1		c.472+4C>T	splice_region intron	N/A	NP_001182723.1	P58418-4
CLRN1	NM_001256819.2		c.*47+1105C>T	intron	N/A	NP_001243748.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CLRN1	ENST00000327047.6	TSL:1 MANE Select	c.433+1105C>T	intron	N/A	ENSP00000322280.1	P58418-3
CLRN1	ENST00000328863.8	TSL:1	c.472+4C>T	splice_region intron	N/A	ENSP00000329158.4	P58418-4
CLRN1	ENST00000295911.6	TSL:1	c.205+1105C>T	intron	N/A	ENSP00000295911.2	P58418-1

Frequencies

GnomAD3 genomes

AF:

0.0319

AC:

4854

AN:

152172

Hom.:

330

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0492

AC:

6602

AN:

134086

AF XY:

0.0452

show subpopulations

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 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.:

AF XY:

0.0174

AC XY:

11847

AN XY:

682154

show subpopulations

African (AFR)

AF:

0.0365

AC:

1152

AN:

31550

American (AMR)

AF:

0.0595

AC:

2122

AN:

35670

Ashkenazi Jewish (ASJ)

AF:

0.00326

AC:

AN:

25130

East Asian (EAS)

AF:

0.310

AC:

11048

AN:

35670

South Asian (SAS)

AF:

0.0405

AC:

3198

AN:

79034

European-Finnish (FIN)

AF:

0.0339

AC:

1147

AN:

33866

Middle Eastern (MID)

AF:

0.0160

AC:

AN:

5690

European-Non Finnish (NFE)

AF:

0.00256

AC:

2757

AN:

1077948

Other (OTH)

AF:

0.0342

AC:

1979

AN:

57830

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

886

1772

2659

3545

4431

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

304

608

912

1216

1520

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0319

AC:

4859

AN:

152290

Hom.:

330

Cov.:

AF XY:

0.0355

AC XY:

2646

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.0370

AC:

1537

AN:

41566

American (AMR)

AF:

0.0413

AC:

632

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00259

AC:

AN:

3472

East Asian (EAS)

AF:

0.317

AC:

1636

AN:

5162

South Asian (SAS)

AF:

0.0605

AC:

292

AN:

4824

European-Finnish (FIN)

AF:

0.0343

AC:

364

AN:

10614

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00459

AC:

312

AN:

68036

Other (OTH)

AF:

0.0279

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

208

417

625

834

1042

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

116

174

232

290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0198

Hom.:

467

Bravo

AF:

0.0345

Asia WGS

AF:

0.182

AC:

632

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Usher syndrome type 3A (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

1.3

(source)

DANN

Benign

0.40

PhyloP100

-0.45

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over