11-32098428-A-G

Variant names:

• chr11-32098428-A-G
• NM_002901.4:c.527A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002901.4(RCN1):​c.527A>G​(p.Lys176Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RCN1 NM_002901.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.26
• Publications: 0 publications found

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]

ENSG00000285283 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27213264).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RCN1	NM_002901.4	c.527A>G	p.Lys176Arg	missense_variant	Exon 3 of 6	ENST00000054950.4	NP_002892.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RCN1	ENST00000054950.4	c.527A>G	p.Lys176Arg	missense_variant	Exon 3 of 6	1	NM_002901.4	ENSP00000054950.4
ENSG00000285283	ENST00000532942.5	c.374A>G	p.Lys125Arg	missense_variant	Exon 3 of 6	2		ENSP00000436422.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.527A>G (p.K176R) alteration is located in exon 3 (coding exon 3) of the RCN1 gene. This alteration results from a A to G substitution at nucleotide position 527, causing the lysine (K) at amino acid position 176 to be replaced by an arginine (R). 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	0.075
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.092	.;.;T;.
Eigen	Benign	-0.087
Eigen_PC	Benign	0.080
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D;D;D;.
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.27	T;T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.88	.;.;L;.
PhyloP100		6.3
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.94	N;N;N;D
REVEL	Benign	0.064
Sift	Benign	0.28	T;T;T;.
Sift4G	Benign	0.30	T;T;T;.
Polyphen		0.022	.;.;B;.
Vest4		0.24, 0.20
MutPred		0.26		.;.;Loss of ubiquitination at K176 (P = 0.0161);.;
MVP		0.80
MPC		0.46
ClinPred		0.74	D
GERP RS		5.5
Varity_R		0.15
gMVP		0.49
Mutation Taster		=79/21	polymorphism

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

Other links and lift over

hg19: chr11-32119974;