6-46456965-T-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001251974.2(RCAN2):c.12A>C(p.Glu4Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0067 in 1,549,912 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0048 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0069 (43 hom.)
• Consequence: RCAN2 NM_001251974.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.141

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00451687).
• BP6: Variant 6-46456965-T-G is Benign according to our data. Variant chr6-46456965-T-G is described in ClinVar as [Benign]. Clinvar id is 2656618.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RCAN2	NM_001251974.2	c.12A>C	p.Glu4Asp	missense_variant	2/5	ENST00000371374.6
RCAN2	NM_001251973.2	c.12A>C	p.Glu4Asp	missense_variant	2/5
RCAN2	XM_011514226.2	c.12A>C	p.Glu4Asp	missense_variant	2/5
RCAN2	XM_024446301.2	c.12A>C	p.Glu4Asp	missense_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RCAN2	ENST00000371374.6	c.12A>C	p.Glu4Asp	missense_variant	2/5	1	NM_001251974.2
RCAN2	ENST00000306764.11	c.12A>C	p.Glu4Asp	missense_variant	2/5	1

Frequencies

GnomAD3 genomes AF: 0.00478 AC: 728 AN: 152214 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.00353

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00732

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00436 AC: 655 AN: 150390 Hom.: 3 AF XY: 0.00431 AC XY: 347 AN XY: 80568

Gnomad AFR exome AF: 0.000991

Gnomad AMR exome AF: 0.00224

Gnomad ASJ exome AF: 0.0202

Gnomad EAS exome AF: 0.000185

Gnomad SAS exome AF: 0.00111

Gnomad FIN exome AF: 0.000944

Gnomad NFE exome AF: 0.00655

Gnomad OTH exome AF: 0.00366

GnomAD4 exome AF: 0.00691 AC: 9653 AN: 1397580 Hom.: 43 Cov.: 30 AF XY: 0.00676 AC XY: 4662 AN XY: 689396

Gnomad4 AFR exome AF: 0.00136

Gnomad4 AMR exome AF: 0.00241

Gnomad4 ASJ exome AF: 0.0193

Gnomad4 EAS exome AF: 0.0000840

Gnomad4 SAS exome AF: 0.00115

Gnomad4 FIN exome AF: 0.00103

Gnomad4 NFE exome AF: 0.00787

Gnomad4 OTH exome AF: 0.00696

GnomAD4 genome AF: 0.00478 AC: 728 AN: 152332 Hom.: 6 Cov.: 32 AF XY: 0.00422 AC XY: 314 AN XY: 74492

Gnomad4 AFR AF: 0.00118

Gnomad4 AMR AF: 0.00353

Gnomad4 ASJ AF: 0.0179

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00188

Gnomad4 NFE AF: 0.00732

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00652 Hom.: 3

Bravo AF: 0.00492

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00752 AC: 29

ExAC AF: 0.00329 AC: 74

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2022

RCAN2: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.78
Cadd	Benign	13
Dann	Uncertain	0.99
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.54	D
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.0045	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.97	N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.14	N;N
REVEL	Benign	0.047
Sift	Benign	0.44	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.11
MutPred		0.18		Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);
MVP		0.53
MPC		0.62
ClinPred		0.0035	T
GERP RS		-1.4
gMVP		0.53

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs191756237; hg19: chr6-46424702;