dbSNP rs745569609: RCN1:p.Leu14Met (chr11-32091236-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002901.4(RCN1):c.40C>A(p.Leu14Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000727 in 1,375,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

RCN1
NM_002901.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.128

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22112581).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RCN1	NM_002901.4 link	c.40C>A	p.Leu14Met	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.40C>A	p.Leu14Met	missense_variant	Exon 1 of 6	1	NM_002901.4	ENSP00000054950.4	Q15293-1
ENSG00000285283	ENST00000532942.5 link	c.102-5908C>A		intron_variant	Intron 1 of 5	2		ENSP00000436422.1
ENSG00000285283	ENST00000530348.5 link	c.-244-5908C>A		intron_variant	Intron 1 of 3	4		ENSP00000436482.1	E9PP27

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.27e-7

AC:

AN:

1375642

Hom.:

Cov.:

AF XY:

0.00000148

AC XY:

AN XY:

677542

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29250

American (AMR)

AF:

0.00

AC:

AN:

33658

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23894

East Asian (EAS)

AF:

0.00

AC:

AN:

34330

South Asian (SAS)

AF:

0.00

AC:

AN:

75934

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47284

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3994

European-Non Finnish (NFE)

AF:

9.34e-7

AC:

AN:

1070394

Other (OTH)

AF:

0.00

AC:

AN:

56904

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000167

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 10, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.40C>A (p.L14M) alteration is located in exon 1 (coding exon 1) of the RCN1 gene. This alteration results from a C to A substitution at nucleotide position 40, causing the leucine (L) at amino acid position 14 to be replaced by a methionine (M). 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

0.17

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.080

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.38

M_CAP

Pathogenic

0.50

MetaRNN

Benign

0.22

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.44

PhyloP100

0.13

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

0.39

REVEL

Benign

0.029

Sift

Benign

0.15

Sift4G

Benign

0.079

Polyphen

0.74

Vest4

0.22

MutPred

0.41

Gain of catalytic residue at L14 (P = 0.007);

MVP

0.40

MPC

0.45

ClinPred

0.094

GERP RS

0.53

PromoterAI

0.25

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.056

gMVP

0.37

Mutation Taster

=82/18

polymorphism

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over