dbSNP rs754621683: RCN1:p.Thr101Asn (chr11-32097191-C-A) – 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.302C>A(p.Thr101Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T101S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RCN1
NM_002901.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.97

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.302C>A	p.Thr101Asn	missense_variant	Exon 2 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.302C>A	p.Thr101Asn	missense_variant	Exon 2 of 6	1	NM_002901.4	ENSP00000054950.4		Q15293-1
ENSG00000285283	ENST00000532942.5 link	c.149C>A	p.Thr50Asn	missense_variant	Exon 2 of 6	2		ENSP00000436422.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000139

AC:

AN:

1444026

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

717878

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000307

AC:

AN:

32582

American (AMR)

AF:

0.00

AC:

AN:

40510

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25242

East Asian (EAS)

AF:

0.00

AC:

AN:

39352

South Asian (SAS)

AF:

0.00

AC:

AN:

82120

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53070

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5680

European-Non Finnish (NFE)

AF:

9.04e-7

AC:

AN:

1105948

Other (OTH)

AF:

0.00

AC:

AN:

59522

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.006664), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.023

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.066

.;T

Eigen

Benign

-0.043

Eigen_PC

Benign

0.020

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.84

T;T

M_CAP

Benign

0.042

MetaRNN

Uncertain

0.49

T;T

MetaSVM

Benign

-0.61

MutationAssessor

Uncertain

2.5

.;M

PhyloP100

6.0

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.98

N;N

REVEL

Benign

0.097

Sift

Benign

0.47

T;T

Sift4G

Benign

0.41

T;T

Polyphen

0.015

.;B

Vest4

0.68

MutPred

0.32

.;Loss of phosphorylation at T101 (P = 0.0605);

MVP

0.74

MPC

0.64

ClinPred

0.83

GERP RS

4.1

Varity_R

0.26

gMVP

0.58

Mutation Taster

=41/59

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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rs754621683

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over