11-32098505-C-A

Variant names:

• chr11-32098505-C-A
• rs1851999490
• NM_002901.4:c.604C>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002901.4(RCN1):​c.604C>A​(p.His202Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 7.91

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

Verdict is Uncertain_significance. Variant got 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	c.604C>A	p.His202Asn	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.604C>A	p.His202Asn	missense_variant	Exon 3 of 6	1	NM_002901.4	ENSP00000054950.4
ENSG00000285283	ENST00000532942.5	c.451C>A	p.His151Asn	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

Jun 08, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.604C>A (p.H202N) alteration is located in exon 3 (coding exon 3) of the RCN1 gene. This alteration results from a C to A substitution at nucleotide position 604, causing the histidine (H) at amino acid position 202 to be replaced by an asparagine (N). 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	0.25
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	.;.;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Benign	0.067	D
MetaRNN	Uncertain	0.58	D;D;D
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	1.6	.;.;L
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-6.1	D;D;D
REVEL	Uncertain	0.34
Sift	Benign	0.085	T;T;T
Sift4G	Benign	0.068	T;T;T
Polyphen		0.22	.;.;B
Vest4		0.67, 0.64
MutPred		0.39		.;.;Loss of catalytic residue at M203 (P = 0.041);
MVP		0.85
MPC		1.4
ClinPred		0.97	D
GERP RS		4.5
Varity_R		0.58
gMVP		0.64

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

LitVar

Other links and lift over

dbSNP: rs1851999490; hg19: chr11-32120051;