rs111033422

Variant names:

• chr3-150972703-T-G
• rs111033422
• NM_174878.3:c.6A>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_174878.3(CLRN1):​c.6A>C​(p.Pro2Pro) 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
• Publications: 5 publications found

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]

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

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

ENSG00000243273 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 48148.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_174878.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLRN1	NM_174878.3	MANE Select	c.6A>C	p.Pro2Pro	synonymous	Exon 1 of 3	NP_777367.1
	CLRN1	NM_001195794.1		c.6A>C	p.Pro2Pro	synonymous	Exon 1 of 4	NP_001182723.1
	CLRN1	NM_001256819.2		c.6A>C	p.Pro2Pro	synonymous	Exon 1 of 4	NP_001243748.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLRN1	ENST00000327047.6	TSL:1 MANE Select	c.6A>C	p.Pro2Pro	synonymous	Exon 1 of 3	ENSP00000322280.1
	CLRN1	ENST00000328863.8	TSL:1	c.6A>C	p.Pro2Pro	synonymous	Exon 1 of 4	ENSP00000329158.4
	SIAH2-AS1	ENST00000465576.1	TSL:1	n.26T>G		non_coding_transcript_exon	Exon 1 of 6

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

GnomAD2 exomes AF: 0.0132 AC: 3318 AN: 251066 AF XY: 0.0120

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 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

African (AFR) AF: 0.129 AC: 4314 AN: 33478

American (AMR) AF: 0.00631 AC: 282 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00145 AC: 38 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0292 AC: 2523 AN: 86258

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53418

Middle Eastern (MID) AF: 0.0106 AC: 61 AN: 5768

European-Non Finnish (NFE) AF: 0.000388 AC: 431 AN: 1112012

Other (OTH) AF: 0.0112 AC: 675 AN: 60396

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

African (AFR) AF: 0.124 AC: 5135 AN: 41546

American (AMR) AF: 0.0107 AC: 163 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.0329 AC: 159 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.000588 AC: 40 AN: 68020

Other (OTH) AF: 0.0227 AC: 48 AN: 2110

Alfa AF: 0.0134 Hom.: 243

Bravo AF: 0.0407

Asia WGS AF: 0.0270 AC: 92 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.00101

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (3)
-	-	2	not specified (2)
-	-	2	Usher syndrome type 3A (2)
-	-	1	Usher syndrome type 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	9.5
DANN	Benign	0.74
PhyloP100		0.31
PromoterAI		-0.018	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs111033422; hg19: chr3-150690490;