4-17515472-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001079827.2(CLRN2):c.206G>A(p.Cys69Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000844 in 1,613,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00087 (0 hom.)
• Consequence: CLRN2 NM_001079827.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.42

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06147474).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLRN2	NM_001079827.2	c.206G>A	p.Cys69Tyr	missense_variant	1/3	ENST00000511148.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLRN2	ENST00000511148.2	c.206G>A	p.Cys69Tyr	missense_variant	1/3	1	NM_001079827.2	P1

Frequencies

GnomAD3 genomes AF: 0.000605 AC: 92 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

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: 0.00103

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000599 AC: 148 AN: 246874 Hom.: 0 AF XY: 0.000648 AC XY: 87 AN XY: 134178

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000903

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.000869 AC: 1270 AN: 1461698 Hom.: 0 Cov.: 31 AF XY: 0.000843 AC XY: 613 AN XY: 727130

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.00103

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00106

Gnomad4 OTH exome AF: 0.000629

GnomAD4 genome AF: 0.000604 AC: 92 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.000524 AC XY: 39 AN XY: 74474

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00103

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000619 Hom.: 0

Bravo AF: 0.000714

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000522 AC: 2

ESP6500EA AF: 0.00121 AC: 10

ExAC AF: 0.000654 AC: 79

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.00130

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

The c.206G>A (p.C69Y) alteration is located in exon 1 (coding exon 1) of the CLRN2 gene. This alteration results from a G to A substitution at nucleotide position 206, causing the cysteine (C) at amino acid position 69 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

CLRN2-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 19, 2023

The CLRN2 c.206G>A variant is predicted to result in the amino acid substitution p.Cys69Tyr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.10% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-17517095-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.080
Cadd	Benign	21
Dann	Benign	0.83
DEOGEN2	Benign	0.0086	T
Eigen	Benign	-0.057
Eigen_PC	Benign	0.15
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.061	T
MetaSVM	Uncertain	0.60	D
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	0.99	D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.11	N
REVEL	Uncertain	0.38
Sift	Benign	1.0	T
Sift4G	Benign	0.94	T
Polyphen		0.0070	B
Vest4		0.41
MVP		0.86
MPC		0.34
ClinPred		0.022	T
GERP RS		5.4
Varity_R		0.25
gMVP		0.91

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

Publications

LitVar

Other links and lift over

dbSNP: rs200819557; hg19: chr4-17517095;