Genetic Variant RCAN3:p.Ala163Val (chr1-24533201-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_013441.4(RCAN3):c.488C>T(p.Ala163Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000106 in 1,605,650 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000076 ( 0 hom. )

Consequence

RCAN3
NM_013441.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.86

Variant links:

Genes affected

RCAN3 (HGNC:3042): (RCAN family member 3) Enables phosphatase binding activity and troponin I binding activity. Predicted to be involved in calcium-mediated signaling. Predicted to be active in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

RCAN3 links:

RCAN3AS (HGNC:39009): (RCAN3 antisense RNA)

RCAN3AS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RCAN3	NM_013441.4 link	c.488C>T	p.Ala163Val	missense_variant	Exon 4 of 5	ENST00000374395.9	NP_038469.1	Q9UKA8-1A0A024RAH2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RCAN3	ENST00000374395.9 link	c.488C>T	p.Ala163Val	missense_variant	Exon 4 of 5	1	NM_013441.4	ENSP00000363516.3		Q9UKA8-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000246

AC:

AN:

243894

Hom.:

AF XY:

0.0000303

AC XY:

AN XY:

132158

show subpopulations

Gnomad AFR exome

AF:

0.000251

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000341

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000896

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000757

AC:

AN:

1453462

Hom.:

Cov.:

AF XY:

0.0000111

AC XY:

AN XY:

722968

show subpopulations

Gnomad4 AFR exome

AF:

0.000121

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000258

Gnomad4 SAS exome

AF:

0.0000236

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.02e-7

Gnomad4 OTH exome

AF:

0.0000500

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000378

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.488C>T (p.A163V) alteration is located in exon 4 (coding exon 3) of the RCAN3 gene. This alteration results from a C to T substitution at nucleotide position 488, causing the alanine (A) at amino acid position 163 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

0.18

BayesDel_addAF

Uncertain

0.098

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

.;T;.;.;T;.;T;.

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.97

.;.;D;D;.;D;D;.

M_CAP

Benign

0.067

MetaRNN

Uncertain

0.71

D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.41

MutationAssessor

Pathogenic

3.1

.;M;.;.;M;.;M;.

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.4

.;.;.;.;D;.;.;.

REVEL

Uncertain

0.31

Sift

Uncertain

0.011

.;.;.;.;D;.;.;.

Sift4G

Uncertain

0.026

D;D;D;D;D;D;D;D

Polyphen

1.0, 1.0

.;D;.;.;D;D;D;.

Vest4

0.63

MutPred

0.60

.;Gain of catalytic residue at A163 (P = 0.0198);.;.;Gain of catalytic residue at A163 (P = 0.0198);.;Gain of catalytic residue at A163 (P = 0.0198);.;

MVP

0.64

MPC

0.67

ClinPred

0.76

GERP RS

4.5

Varity_R

0.37

gMVP

0.45

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