Variant 6-46246874-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001251974.2(RCAN2):c.445C>G(p.Pro149Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,453,354 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

RCAN2
NM_001251974.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.50

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 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.924

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RCAN2	NM_001251974.2 linkuse as main transcript	c.445C>G	p.Pro149Ala	missense_variant	4/5	ENST00000371374.6	NP_001238903.1
LOC105375079	XR_001743802.3 linkuse as main transcript	n.291+1878G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RCAN2	ENST00000371374.6 linkuse as main transcript	c.445C>G	p.Pro149Ala	missense_variant	4/5	1	NM_001251974.2	ENSP00000360425		Q14206-2
RCAN2	ENST00000306764.11 linkuse as main transcript	c.445C>G	p.Pro149Ala	missense_variant	4/5	1		ENSP00000305223		Q14206-2
RCAN2	ENST00000330430.10 linkuse as main transcript	c.307C>G	p.Pro103Ala	missense_variant	3/4	1		ENSP00000329454	P1	Q14206-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000411

AC:

AN:

243160

Hom.:

AF XY:

0.00

AC XY:

AN XY:

131764

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:

0.00000905

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1453354

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

721946

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:

0.00000271

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Aug 08, 2022

The c.307C>G (p.P103A) alteration is located in exon 3 (coding exon 3) of the RCAN2 gene. This alteration results from a C to G substitution at nucleotide position 307, causing the proline (P) at amino acid position 103 to be replaced by an alanine (A). 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

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

D;.;.;D

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;.;D;D

M_CAP

Benign

0.049

MetaRNN

Pathogenic

0.92

D;D;D;D

MetaSVM

Uncertain

0.18

MutationAssessor

Pathogenic

3.9

H;.;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-7.9

D;D;D;.

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

D;D;D;.

Sift4G

Uncertain

0.0050

D;D;D;D

Polyphen

0.99

D;P;P;.

Vest4

0.83

MutPred

0.78

Loss of catalytic residue at P102 (P = 0.0138);.;.;Loss of catalytic residue at P102 (P = 0.0138);

MVP

0.71

MPC

1.7

ClinPred

1.0

GERP RS

5.7

Varity_R

0.87

gMVP

0.75

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