Genetic Variant RCN1:p.Leu22Pro (chr11-32091261-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002901.4(RCN1):c.65T>C(p.Leu22Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000578 in 1,385,036 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000058 ( 0 hom. )

Consequence

RCN1
NM_002901.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.05

Publications

0 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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RCN1	NM_002901.4 link	c.65T>C	p.Leu22Pro	missense_variant	Exon 1 of 6	ENST00000054950.4	NP_002892.1	Q15293-1V9HW95

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RCN1	ENST00000054950.4 link	c.65T>C	p.Leu22Pro	missense_variant	Exon 1 of 6	1	NM_002901.4	ENSP00000054950.4	Q15293-1
ENSG00000285283	ENST00000532942.5 link	c.102-5883T>C		intron_variant	Intron 1 of 5	2		ENSP00000436422.1
ENSG00000285283	ENST00000530348.5 link	c.-244-5883T>C		intron_variant	Intron 1 of 3	4		ENSP00000436482.1	E9PP27

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000578

AC:

AN:

1385036

Hom.:

Cov.:

AF XY:

0.00000586

AC XY:

AN XY:

682548

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29996

American (AMR)

AF:

0.00

AC:

AN:

34814

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24708

East Asian (EAS)

AF:

0.00

AC:

AN:

34818

South Asian (SAS)

AF:

0.00

AC:

AN:

77786

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47796

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4044

European-Non Finnish (NFE)

AF:

0.00000745

AC:

AN:

1073784

Other (OTH)

AF:

0.00

AC:

AN:

57290

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000285

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 14, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.65T>C (p.L22P) alteration is located in exon 1 (coding exon 1) of the RCN1 gene. This alteration results from a T to C substitution at nucleotide position 65, causing the leucine (L) at amino acid position 22 to be replaced by a proline (P). 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

0.16

BayesDel_addAF

Benign

-0.00074

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.28

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.13

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.40

M_CAP

Pathogenic

0.97

MetaRNN

Uncertain

0.65

MetaSVM

Benign

-0.74

MutationAssessor

Uncertain

2.2

PhyloP100

4.0

PrimateAI

Pathogenic

0.93

PROVEAN

Uncertain

-3.1

REVEL

Benign

0.21

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.023

Polyphen

0.0030

Vest4

0.63

MutPred

0.34

Loss of MoRF binding (P = 0.094);

MVP

0.46

MPC

0.76

ClinPred

0.96

GERP RS

2.5

PromoterAI

0.023

Neutral

(source)

Varity_R

0.78

gMVP

0.87

Mutation Taster

=46/54

disease causing

(source)

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

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11-32091261-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over