Genetic Variant RCN1:p.Ala153Thr (chr11-32098358-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_StrongBS2

The NM_002901.4(RCN1):c.457G>A(p.Ala153Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0107 in 1,609,938 control chromosomes in the GnomAD database, including 127 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0076 ( 6 hom., cov: 32)

Exomes 𝑓: 0.011 ( 121 hom. )

Consequence

RCN1
NM_002901.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 3.40

Publications

6 publications found

Variant links:

Genes affected

RCN1 (HGNC:9934): (reticulocalbin 1) Reticulocalbin 1 is a calcium-binding protein located in the lumen of the ER. The protein contains six conserved regions with similarity to a high affinity Ca(+2)-binding motif, the EF-hand. High conservation of amino acid residues outside of these motifs, in comparison to mouse reticulocalbin, is consistent with a possible biochemical function besides that of calcium binding. In human endothelial and prostate cancer cell lines this protein localizes to the plasma membrane.[provided by RefSeq, Jan 2009]

RCN1 links:

ENSG00000285283 (HGNC:):

ENSG00000285283 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP6

Variant 11-32098358-G-A is Benign according to our data. Variant chr11-32098358-G-A is described in ClinVar as [Benign]. Clinvar id is 782955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RCN1	NM_002901.4 link	c.457G>A	p.Ala153Thr	missense_variant	Exon 3 of 6	ENST00000054950.4	NP_002892.1	Q15293-1V9HW95

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RCN1	ENST00000054950.4 link	c.457G>A	p.Ala153Thr	missense_variant	Exon 3 of 6	1	NM_002901.4	ENSP00000054950.4		Q15293-1
ENSG00000285283	ENST00000532942.5 link	c.304G>A	p.Ala102Thr	missense_variant	Exon 3 of 6	2		ENSP00000436422.1

Frequencies

GnomAD3 genomes

AF:

0.00757

AC:

1152

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00254

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00563

Gnomad ASJ

AF:

0.00893

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00434

Gnomad FIN

AF:

0.00358

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0127

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00672

AC:

1659

AN:

246748

AF XY:

0.00714

show subpopulations

Gnomad AFR exome

AF:

0.00229

Gnomad AMR exome

AF:

0.00311

Gnomad ASJ exome

AF:

0.00764

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00488

Gnomad NFE exome

AF:

0.00989

Gnomad OTH exome

AF:

0.00751

GnomAD4 exome

AF:

0.0110

AC:

16094

AN:

1457688

Hom.:

121

Cov.:

AF XY:

0.0109

AC XY:

7875

AN XY:

724986

show subpopulations

African (AFR)

AF:

0.00181

AC:

AN:

33232

American (AMR)

AF:

0.00306

AC:

134

AN:

43780

Ashkenazi Jewish (ASJ)

AF:

0.00690

AC:

179

AN:

25944

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39662

South Asian (SAS)

AF:

0.00563

AC:

480

AN:

85276

European-Finnish (FIN)

AF:

0.00496

AC:

265

AN:

53378

Middle Eastern (MID)

AF:

0.00274

AC:

AN:

5484

European-Non Finnish (NFE)

AF:

0.0129

AC:

14319

AN:

1110754

Other (OTH)

AF:

0.0106

AC:

640

AN:

60178

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

714

1428

2142

2856

3570

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00757

AC:

1152

AN:

152250

Hom.:

Cov.:

AF XY:

0.00700

AC XY:

521

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.00250

AC:

104

AN:

41538

American (AMR)

AF:

0.00562

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00893

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.00435

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00358

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0127

AC:

861

AN:

68016

Other (OTH)

AF:

0.00474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

113

170

226

283

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00995

Hom.:

Bravo

AF:

0.00682

TwinsUK

AF:

0.0127

AC:

ALSPAC

AF:

0.0179

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.0129

AC:

111

ExAC

AF:

0.00642

AC:

779

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0113

EpiControl

AF:

0.0116

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.064

.;T

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.81

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.71

T;T

MetaRNN

Benign

0.0076

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

.;L

PhyloP100

3.4

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.39

N;N

REVEL

Benign

0.17

Sift

Benign

0.49

T;T

Sift4G

Benign

0.47

T;T

Polyphen

0.0060

.;B

Vest4

0.088

MVP

0.40

MPC

0.45

ClinPred

0.011

GERP RS

0.35

Varity_R

0.027

gMVP

0.32

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.32

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.32

Position offset: 22

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

Publications

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11-32098358-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over