3-150941608-C-G

Position:

• chr3-150941608-C-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The ENST00000327047.6(CLRN1):​c.407G>C​(p.Gly136Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G136E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CLRN1 ENST00000327047.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.72

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a transmembrane_region Helical (size 20) in uniprot entity CLRN1_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in ENST00000327047.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-150941608-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLRN1	NM_174878.3	c.407G>C	p.Gly136Ala	missense_variant	2/3	ENST00000327047.6	NP_777367.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLRN1	ENST00000327047.6	c.407G>C	p.Gly136Ala	missense_variant	2/3	1	NM_174878.3	ENSP00000322280	P1
	ENST00000469268.1	n.235+50738C>G		intron_variant, non_coding_transcript_variant		4
CLRN1-AS1	ENST00000476886.5	n.123+89002C>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251276 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135810

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 SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461754 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727180

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	.;D;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Uncertain	2.2	.;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.7	D;D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.029	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.98
MutPred		0.87		.;Gain of catalytic residue at G136 (P = 0.1004);Gain of catalytic residue at G136 (P = 0.1004);
MVP		0.95
MPC		0.17
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.92
gMVP		0.93

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

Publications

LitVar

Other links and lift over

dbSNP: rs779258184; hg19: chr3-150659395;