6-46246910-G-A

Position:

• chr6-46246910-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001251974.2(RCAN2):​c.409C>T​(p.Pro137Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,413,422 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RCAN2 NM_001251974.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.45

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.122178555).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RCAN2	NM_001251974.2	c.409C>T	p.Pro137Ser	missense_variant	4/5	ENST00000371374.6	NP_001238903.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RCAN2	ENST00000371374.6	c.409C>T	p.Pro137Ser	missense_variant	4/5	1	NM_001251974.2	ENSP00000360425.1
RCAN2	ENST00000306764.11	c.409C>T	p.Pro137Ser	missense_variant	4/5	1		ENSP00000305223.7
RCAN2	ENST00000330430.10	c.271C>T	p.Pro91Ser	missense_variant	3/4	1		ENSP00000329454.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1413422 Hom.: 0 Cov.: 30 AF XY: 0.00000143 AC XY: 1 AN XY: 697938

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: 0.00000184

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

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

Dec 10, 2024

The c.271C>T (p.P91S) alteration is located in exon 3 (coding exon 3) of the RCAN2 gene. This alteration results from a C to T substitution at nucleotide position 271, causing the proline (P) at amino acid position 91 to be replaced by a serine (S). 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	0.070
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	19
DANN	Benign	0.87
DEOGEN2	Benign	0.20	T;.;.;T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.052
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.85	D;.;D;D
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.24	N;.;.;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.1	N;D;D;.
REVEL	Benign	0.091
Sift	Benign	0.55	T;T;T;.
Sift4G	Benign	0.33	T;T;T;T
Polyphen		0.0010	B;B;B;.
Vest4		0.043
MutPred		0.59		Gain of sheet (P = 0.0827);.;.;Gain of sheet (P = 0.0827);
MVP		0.47
MPC		0.69
ClinPred		0.32	T
GERP RS		3.9
Varity_R		0.072
gMVP		0.30

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

Other links and lift over

dbSNP: rs947146198; hg19: chr6-46214647;