6-46246905-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001251974.2(RCAN2):c.414G>C(p.Glu138Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000028 in 1,430,264 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

RCAN2
NM_001251974.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.59

Variant links:

Genes affected

RCAN2 (HGNC:3041): (regulator of calcineurin 2) This gene encodes a member of the regulator of calcineurin (RCAN) protein family. These proteins play a role in many physiological processes by binding to the catalytic domain of calcineurin A, inhibiting calcineurin-mediated nuclear translocation of the transcription factor NFATC1. Expression of this gene in skin fibroblasts is upregulated by thyroid hormone, and the encoded protein may also play a role in endothelial cell function and angiogenesis. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Oct 2011]

RCAN2 links:

LOC105375079 (HGNC:):

LOC105375079 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12187752).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RCAN2	NM_001251974.2 linkuse as main transcript	c.414G>C	p.Glu138Asp	missense_variant	4/5	ENST00000371374.6
LOC105375079	XR_001743802.3 linkuse as main transcript	n.291+1909C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RCAN2	ENST00000371374.6 linkuse as main transcript	c.414G>C	p.Glu138Asp	missense_variant	4/5	1	NM_001251974.2		Q14206-2
RCAN2	ENST00000306764.11 linkuse as main transcript	c.414G>C	p.Glu138Asp	missense_variant	4/5	1			Q14206-2
RCAN2	ENST00000330430.10 linkuse as main transcript	c.276G>C	p.Glu92Asp	missense_variant	3/4	1		P1	Q14206-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000887

AC:

AN:

225492

Hom.:

AF XY:

0.0000164

AC XY:

AN XY:

121590

show subpopulations

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000193

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000280

AC:

AN:

1430264

Hom.:

Cov.:

AF XY:

0.00000424

AC XY:

AN XY:

707702

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000365

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 01, 2023

The c.276G>C (p.E92D) alteration is located in exon 3 (coding exon 3) of the RCAN2 gene. This alteration results from a G to C substitution at nucleotide position 276, causing the glutamic acid (E) at amino acid position 92 to be replaced by an aspartic acid (D). 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

0.076

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.54

Cadd

Benign

Dann

Benign

0.96

DEOGEN2

Benign

0.075

T;.;.;T

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.034

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.72

T;.;T;T

M_CAP

Benign

0.0030

MetaRNN

Benign

0.12

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.38

N;.;.;.

MutationTaster

Benign

0.95

D;D;D;D

PrimateAI

Uncertain

0.67

PROVEAN

Benign

0.040

N;N;N;.

REVEL

Benign

0.075

Sift

Benign

0.61

T;T;T;.

Sift4G

Benign

0.63

T;T;T;T

Polyphen

0.0010

B;B;B;.

Vest4

0.066

MutPred

0.43

Gain of sheet (P = 0.0149);.;.;Gain of sheet (P = 0.0149);

MVP

0.53

MPC

0.63

ClinPred

0.23

GERP RS

3.8

Varity_R

0.12

gMVP

0.19

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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