Genetic Variant CLRN2:p.Ala158Val (chr4-17526856-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001079827.2(CLRN2):c.473C>T(p.Ala158Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000186 in 1,613,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00049 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

CLRN2
NM_001079827.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.33

Variant links:

Genes affected

CLRN2 (HGNC:33939): (clarin 2) This gene belongs to the clarin family of genes. The clarins appear to belong to a large superfamily of small integral membrane glycoproteins with four transmembrane domains. The exact function of this gene is unknown. [provided by RefSeq, Oct 2008]

CLRN2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.26543126).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLRN2	NM_001079827.2 link	c.473C>T	p.Ala158Val	missense_variant	Exon 3 of 3	ENST00000511148.2	NP_001073296.1	A0PK11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLRN2	ENST00000511148.2 link	c.473C>T	p.Ala158Val	missense_variant	Exon 3 of 3	1	NM_001079827.2	ENSP00000424711.2		A0PK11

Frequencies

GnomAD3 genomes

AF:

0.000493

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00159

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000882

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000963

AC:

AN:

249190

Hom.:

AF XY:

0.0000888

AC XY:

AN XY:

135192

show subpopulations

Gnomad AFR exome

AF:

0.000969

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000708

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000155

AC:

226

AN:

1461690

Hom.:

Cov.:

AF XY:

0.000151

AC XY:

110

AN XY:

727122

show subpopulations

Gnomad4 AFR exome

AF:

0.00179

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000123

Gnomad4 OTH exome

AF:

0.000381

GnomAD4 genome

AF:

0.000493

AC:

AN:

152280

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.00159

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000153

Hom.:

Bravo

AF:

0.000552

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00147

AC:

ESP6500EA

AF:

0.000238

AC:

ExAC

AF:

0.0000992

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 16, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.473C>T (p.A158V) alteration is located in exon 3 (coding exon 3) of the CLRN2 gene. This alteration results from a C to T substitution at nucleotide position 473, causing the alanine (A) at amino acid position 158 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.13

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.059

Eigen

Benign

0.095

Eigen_PC

Benign

0.038

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.82

M_CAP

Benign

0.065

MetaRNN

Benign

0.27

MetaSVM

Uncertain

0.26

MutationAssessor

Benign

1.6

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.99

REVEL

Uncertain

0.36

Sift

Benign

0.067

Sift4G

Benign

0.099

Polyphen

0.91

Vest4

0.57

MVP

0.74

MPC

0.23

ClinPred

0.076

GERP RS

4.9

Varity_R

0.091

gMVP

0.64

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over