6-46248849-G-T

Position:

• chr6-46248849-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001251974.2(RCAN2):​c.273C>A​(p.Phe91Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 29)
• Consequence: RCAN2 NM_001251974.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.05

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]

LOC105375079 (HGNC:):

ACMG classification

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, 0.848

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RCAN2	NM_001251974.2	c.273C>A	p.Phe91Leu	missense_variant	3/5	ENST00000371374.6	NP_001238903.1
LOC105375079	XR_001743802.3	n.291+3853G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RCAN2	ENST00000371374.6	c.273C>A	p.Phe91Leu	missense_variant	3/5	1	NM_001251974.2	ENSP00000360425
RCAN2	ENST00000306764.11	c.273C>A	p.Phe91Leu	missense_variant	3/5	1		ENSP00000305223
RCAN2	ENST00000330430.10	c.135C>A	p.Phe45Leu	missense_variant	2/4	1		ENSP00000329454	P1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 29

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 13, 2023

The c.135C>A (p.F45L) alteration is located in exon 2 (coding exon 2) of the RCAN2 gene. This alteration results from a C to A substitution at nucleotide position 135, causing the phenylalanine (F) at amino acid position 45 to be replaced by a leucine (L). 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	0.97
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D;.;.;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.087
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.93	D;.;D;D
M_CAP	Benign	0.0064	T
MetaRNN	Pathogenic	0.85	D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.8	M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.3	D;D;D;.
REVEL	Benign	0.24
Sift	Uncertain	0.015	D;D;D;.
Sift4G	Benign	0.088	T;T;T;T
Polyphen		0.0020	B;B;B;.
Vest4		0.67
MutPred		0.90		Loss of sheet (P = 0.0315);.;.;Loss of sheet (P = 0.0315);
MVP		0.55
MPC		0.81
ClinPred		0.98	D
GERP RS		0.021
Varity_R		0.58
gMVP		0.59

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-46216586;