rs144307253

Variant names:

• chr11-32097163-G-A
• rs144307253
• NM_002901.4:c.274G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-32097163-G-A
• chr11-32097163-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM1

The NM_002901.4(RCN1):​c.274G>A​(p.Asp92Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00019 in 1,521,276 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00019 (1 hom.)
• Consequence: RCN1 NM_002901.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.96
• Publications: 4 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 2 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity RCN1_HUMAN

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RCN1	NM_002901.4	c.274G>A	p.Asp92Asn	missense_variant	Exon 2 of 6	ENST00000054950.4	NP_002892.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RCN1	ENST00000054950.4	c.274G>A	p.Asp92Asn	missense_variant	Exon 2 of 6	1	NM_002901.4	ENSP00000054950.4
ENSG00000285283	ENST00000532942.5	c.121G>A	p.Asp41Asn	missense_variant	Exon 2 of 6	2		ENSP00000436422.1

Frequencies

GnomAD3 genomes AF: 0.000176 AC: 26 AN: 148142 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00290

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00980

Gnomad NFE AF: 0.000163

Gnomad OTH AF: 0.000977

GnomAD2 exomes AF: 0.000188 AC: 34 AN: 180910 AF XY: 0.000164

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000531

Gnomad ASJ exome AF: 0.00325

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000136

Gnomad OTH exome AF: 0.000488

GnomAD4 exome AF: 0.000192 AC: 263 AN: 1373042 Hom.: 1 Cov.: 35 AF XY: 0.000205 AC XY: 139 AN XY: 677960

African (AFR) AF: 0.000401 AC: 12 AN: 29938

American (AMR) AF: 0.0000723 AC: 2 AN: 27656

Ashkenazi Jewish (ASJ) AF: 0.00304 AC: 66 AN: 21704

East Asian (EAS) AF: 0.00 AC: 0 AN: 37776

South Asian (SAS) AF: 0.0000284 AC: 2 AN: 70402

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50656

Middle Eastern (MID) AF: 0.00168 AC: 9 AN: 5344

European-Non Finnish (NFE) AF: 0.000123 AC: 132 AN: 1073250

Other (OTH) AF: 0.000710 AC: 40 AN: 56316

GnomAD4 genome AF: 0.000175 AC: 26 AN: 148234 Hom.: 0 Cov.: 30 AF XY: 0.000167 AC XY: 12 AN XY: 71902

African (AFR) AF: 0.00 AC: 0 AN: 40278

American (AMR) AF: 0.00 AC: 0 AN: 14694

Ashkenazi Jewish (ASJ) AF: 0.00290 AC: 10 AN: 3452

East Asian (EAS) AF: 0.00 AC: 0 AN: 5004

South Asian (SAS) AF: 0.00 AC: 0 AN: 4664

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9380

Middle Eastern (MID) AF: 0.0106 AC: 3 AN: 284

European-Non Finnish (NFE) AF: 0.000163 AC: 11 AN: 67510

Other (OTH) AF: 0.000971 AC: 2 AN: 2060

Alfa AF: 0.000549 Hom.: 1

Bravo AF: 0.000151

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000247 AC: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 01, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.274G>A (p.D92N) alteration is located in exon 2 (coding exon 2) of the RCN1 gene. This alteration results from a G to A substitution at nucleotide position 274, causing the aspartic acid (D) at amino acid position 92 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	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	.;T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Uncertain	0.55	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	.;H
PhyloP100		10
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-4.3	D;D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.97	.;D
Vest4		0.93
MVP		0.99
MPC		0.58
ClinPred		0.81	D
GERP RS		5.0
Varity_R		0.54
gMVP		0.88
Mutation Taster		=37/63	disease causing

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

dbSNP: rs144307253; hg19: chr11-32118709; COSMIC: COSV50014257; COSMIC: COSV50014257;