3-150972491-T-C

Variant names:

• chr3-150972491-T-C
• rs201008540
• NM_174878.3:c.218A>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_174878.3(CLRN1):​c.218A>G​(p.Gln73Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000273 in 1,614,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: CLRN1 NM_174878.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 7.52
• 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]

ENSG00000243273 (HGNC:):

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

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

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3143114).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLRN1	NM_174878.3	MANE Select	c.218A>G	p.Gln73Arg	missense	Exon 1 of 3	NP_777367.1	P58418-3
	CLRN1	NM_001195794.1		c.218A>G	p.Gln73Arg	missense	Exon 1 of 4	NP_001182723.1	P58418-4
	CLRN1	NM_001256819.2		c.218A>G	p.Gln73Arg	missense	Exon 1 of 4	NP_001243748.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLRN1	ENST00000327047.6	TSL:1 MANE Select	c.218A>G	p.Gln73Arg	missense	Exon 1 of 3	ENSP00000322280.1	P58418-3
	CLRN1	ENST00000328863.8	TSL:1	c.218A>G	p.Gln73Arg	missense	Exon 1 of 4	ENSP00000329158.4	P58418-4
	CLRN1	ENST00000468836.2	TSL:3	c.194A>G	p.Gln65Arg	missense	Exon 1 of 4	ENSP00000419892.2	C9JYI2

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152182 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000191 AC: 48 AN: 251476 AF XY: 0.000177

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000378

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000285 AC: 417 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.000303 AC XY: 220 AN XY: 727246

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.000134 AC: 6 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000351 AC: 390 AN: 1112010

Other (OTH) AF: 0.000331 AC: 20 AN: 60396

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152300 Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8 AN XY: 74462

African (AFR) AF: 0.0000722 AC: 3 AN: 41562

American (AMR) AF: 0.0000654 AC: 1 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000257 Hom.: 0

Bravo AF: 0.000196

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000198 AC: 24

EpiCase AF: 0.000327

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not specified (2)
-	2	-	Usher syndrome type 3A (2)
-	1	-	not provided (1)
-	1	-	Retinal dystrophy (1)
-	1	-	Retinitis pigmentosa;C3280041:Retinitis pigmentosa 61;C5779850:Usher syndrome type 3A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.31	T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.5
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.58
Sift	Benign	0.12	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.64
MVP		0.81
MPC		0.12
ClinPred		0.25	T
GERP RS		5.5
PromoterAI		0.014	Neutral
Varity_R		0.27
gMVP		0.78
Mutation Taster		=52/48	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201008540; hg19: chr3-150690278;