Variant 21-34521637-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_004414.7(RCAN1):c.448C>T(p.His150Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000223 in 1,613,050 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00021 ( 1 hom. )

Consequence

RCAN1
NM_004414.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.71

Variant links:

Genes affected

RCAN1 (HGNC:3040): (regulator of calcineurin 1) The protein encoded by this gene interacts with calcineurin A and inhibits calcineurin-dependent signaling pathways, possibly affecting central nervous system development. This gene is located in the minimal candidate region for the Down syndrome phenotype, and is overexpressed in the brain of Down syndrome fetuses. Chronic overexpression of this gene may lead to neurofibrillary tangles such as those associated with Alzheimer disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2013]

RCAN1 links:

ENSG00000288711 (HGNC:):

ENSG00000288711 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.046788186).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RCAN1	NM_004414.7 link	c.448C>T	p.His150Tyr	missense_variant	3/4	ENST00000313806.9	NP_004405.3	P53805-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RCAN1	ENST00000313806.9 link	c.448C>T	p.His150Tyr	missense_variant	3/4	1	NM_004414.7	ENSP00000320768.4		P53805-1
ENSG00000288711	ENST00000684114.1 link	n.349C>T		non_coding_transcript_exon_variant	3/5			ENSP00000507841.1		A0A804HKA1

Frequencies

GnomAD3 genomes

AF:

0.000335

AC:

AN:

152262

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000964

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00203

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000306

AC:

AN:

248646

Hom.:

AF XY:

0.000313

AC XY:

AN XY:

134268

show subpopulations

Gnomad AFR exome

AF:

0.000248

Gnomad AMR exome

AF:

0.000959

Gnomad ASJ exome

AF:

0.00132

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000196

Gnomad OTH exome

AF:

0.000663

GnomAD4 exome

AF:

0.000211

AC:

308

AN:

1460670

Hom.:

Cov.:

AF XY:

0.000223

AC XY:

162

AN XY:

726576

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.00103

Gnomad4 ASJ exome

AF:

0.000926

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000168

Gnomad4 OTH exome

AF:

0.000597

GnomAD4 genome

AF:

0.000335

AC:

AN:

152380

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

AN XY:

74524

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.00203

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.000295

Hom.:

Bravo

AF:

0.000540

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000214

AC:

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

Mar 26, 2024

The c.448C>T (p.H150Y) alteration is located in exon 3 (coding exon 3) of the RCAN1 gene. This alteration results from a C to T substitution at nucleotide position 448, causing the histidine (H) at amino acid position 150 to be replaced by a tyrosine (Y). 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

0.25

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.48

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

.;T;.;.;.;.;.;.;D;.

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.90

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

M_CAP

Benign

0.0040

MetaRNN

Benign

0.047

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.56

MutationAssessor

Benign

1.2

.;.;.;.;.;.;.;.;L;.

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-2.7

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

REVEL

Uncertain

0.29

Sift

Benign

0.34

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

Sift4G

Benign

0.36

T;T;T;T;T;T;T;T;T;T

Polyphen

0.0010, 0.17

.;.;.;.;.;.;.;B;B;.

Vest4

0.21

MVP

0.27

MPC

1.3

ClinPred

0.099

GERP RS

5.6

Varity_R

0.40

gMVP

0.64

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