Genetic Variant CLRN2:p.Leu113Val (chr4-17522947-C-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001079827.2(CLRN2):c.337C>G(p.Leu113Val) variant causes a missense change. The variant allele was found at a frequency of 0.129 in 1,613,840 control chromosomes in the GnomAD database, including 14,301 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.10 ( 966 hom., cov: 33)

Exomes 𝑓: 0.13 ( 13335 hom. )

Consequence

CLRN2
NM_001079827.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 3.97

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018548369).

BP6

Variant 4-17522947-C-G is Benign according to our data. Variant chr4-17522947-C-G is described in ClinVar as [Benign]. Clinvar id is 1286756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLRN2	NM_001079827.2 link	c.337C>G	p.Leu113Val	missense_variant	Exon 2 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.337C>G	p.Leu113Val	missense_variant	Exon 2 of 3	1	NM_001079827.2	ENSP00000424711.2		A0PK11

Frequencies

GnomAD3 genomes

AF:

0.103

AC:

15687

AN:

152140

Hom.:

962

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0267

Gnomad AMI

AF:

0.192

Gnomad AMR

AF:

0.119

Gnomad ASJ

AF:

0.193

Gnomad EAS

AF:

0.0908

Gnomad SAS

AF:

0.141

Gnomad FIN

AF:

0.139

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.134

Gnomad OTH

AF:

0.0899

GnomAD3 exomes

AF:

0.130

AC:

32385

AN:

249170

Hom.:

2322

AF XY:

0.131

AC XY:

17760

AN XY:

135162

show subpopulations

Gnomad AFR exome

AF:

0.0203

Gnomad AMR exome

AF:

0.145

Gnomad ASJ exome

AF:

0.197

Gnomad EAS exome

AF:

0.0950

Gnomad SAS exome

AF:

0.138

Gnomad FIN exome

AF:

0.140

Gnomad NFE exome

AF:

0.136

Gnomad OTH exome

AF:

0.130

GnomAD4 exome

AF:

0.132

AC:

192340

AN:

1461582

Hom.:

13335

Cov.:

AF XY:

0.132

AC XY:

96225

AN XY:

727064

show subpopulations

Gnomad4 AFR exome

AF:

0.0183

Gnomad4 AMR exome

AF:

0.147

Gnomad4 ASJ exome

AF:

0.202

Gnomad4 EAS exome

AF:

0.0845

Gnomad4 SAS exome

AF:

0.137

Gnomad4 FIN exome

AF:

0.137

Gnomad4 NFE exome

AF:

0.134

Gnomad4 OTH exome

AF:

0.130

GnomAD4 genome

AF:

0.103

AC:

15699

AN:

152258

Hom.:

966

Cov.:

AF XY:

0.104

AC XY:

7707

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.0266

Gnomad4 AMR

AF:

0.119

Gnomad4 ASJ

AF:

0.193

Gnomad4 EAS

AF:

0.0906

Gnomad4 SAS

AF:

0.142

Gnomad4 FIN

AF:

0.139

Gnomad4 NFE

AF:

0.134

Gnomad4 OTH

AF:

0.0899

Alfa

AF:

0.131

Hom.:

1068

Bravo

AF:

0.0988

TwinsUK

AF:

0.128

AC:

473

ALSPAC

AF:

0.123

AC:

474

ESP6500AA

AF:

0.0297

AC:

127

ESP6500EA

AF:

0.134

AC:

1141

ExAC

AF:

0.128

AC:

15497

Asia WGS

AF:

0.117

AC:

406

AN:

3478

EpiCase

AF:

0.127

EpiControl

AF:

0.121

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Apr 27, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 31448880) -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.040

Eigen

Benign

0.10

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.70

MetaRNN

Benign

0.0019

MetaSVM

Benign

-0.91

MutationAssessor

Benign

2.0

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.7

REVEL

Uncertain

0.34

Sift

Benign

0.089

Sift4G

Benign

0.31

Polyphen

0.90

Vest4

0.14

MPC

0.70

ClinPred

0.030

GERP RS

4.2

Varity_R

0.24

gMVP

0.78

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

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