3-150972617-G-C

Variant names:

• chr3-150972617-G-C
• rs374390376
• NM_174878.3:c.92C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM5

The NM_174878.3(CLRN1):​c.92C>G​(p.Pro31Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000601 in 1,614,092 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P31L) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000065 (0 hom.)
• Consequence: CLRN1 NM_174878.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 2.93
• Publications: 7 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: Uncertain_significance. The variant received 2 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-150972617-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 30575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.92C>G	p.Pro31Arg	missense	Exon 1 of 3	NP_777367.1	P58418-3
	CLRN1	NM_001195794.1		c.92C>G	p.Pro31Arg	missense	Exon 1 of 4	NP_001182723.1	P58418-4
	CLRN1	NM_001256819.2		c.92C>G	p.Pro31Arg	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.92C>G	p.Pro31Arg	missense	Exon 1 of 3	ENSP00000322280.1	P58418-3
	CLRN1	ENST00000328863.8	TSL:1	c.92C>G	p.Pro31Arg	missense	Exon 1 of 4	ENSP00000329158.4	P58418-4
	CLRN1	ENST00000468836.2	TSL:3	c.68C>G	p.Pro23Arg	missense	Exon 1 of 4	ENSP00000419892.2	C9JYI2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251422 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000650 AC: 95 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.0000660 AC XY: 48 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 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: 0.0000845 AC: 94 AN: 1112012

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152198 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74348

African (AFR) AF: 0.0000241 AC: 1 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000805 Hom.: 0

Bravo AF: 0.0000151

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.080	D
MetaRNN	Uncertain	0.50	D
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.9
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.35
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.20	T
Polyphen		0.95	P
Vest4		0.21
MVP		0.88
MPC		0.15
ClinPred		0.91	D
GERP RS		4.4
PromoterAI		0.0087	Neutral
Varity_R		0.13
gMVP		0.58
Mutation Taster		=25/75	disease causing

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: rs374390376; hg19: chr3-150690404;