Genetic Variant NM_002901.4:c.274G>A (chr11-32097163-G-A) – ACMG Classification: Uncertain_significance (2 pts)

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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.96

Publications

4 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 link	c.274G>A	p.Asp92Asn	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.274G>A	p.Asp92Asn	missense_variant	Exon 2 of 6	1	NM_002901.4	ENSP00000054950.4		Q15293-1
ENSG00000285283	ENST00000532942.5 link	c.121G>A	p.Asp41Asn	missense_variant	Exon 2 of 6	2		ENSP00000436422.1

Frequencies

GnomAD3 genomes

AF:

0.000176

AC:

AN:

148142

Hom.:

Cov.:

show subpopulations

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:

AN:

180910

AF XY:

0.000164

show subpopulations

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.:

Cov.:

AF XY:

0.000205

AC XY:

139

AN XY:

677960

show subpopulations

African (AFR)

AF:

0.000401

AC:

AN:

29938

American (AMR)

AF:

0.0000723

AC:

AN:

27656

Ashkenazi Jewish (ASJ)

AF:

0.00304

AC:

AN:

21704

East Asian (EAS)

AF:

0.00

AC:

AN:

37776

South Asian (SAS)

AF:

0.0000284

AC:

AN:

70402

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50656

Middle Eastern (MID)

AF:

0.00168

AC:

AN:

5344

European-Non Finnish (NFE)

AF:

0.000123

AC:

132

AN:

1073250

Other (OTH)

AF:

0.000710

AC:

AN:

56316

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000175

AC:

AN:

148234

Hom.:

Cov.:

AF XY:

0.000167

AC XY:

AN XY:

71902

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40278

American (AMR)

AF:

0.00

AC:

AN:

14694

Ashkenazi Jewish (ASJ)

AF:

0.00290

AC:

AN:

3452

East Asian (EAS)

AF:

0.00

AC:

AN:

5004

South Asian (SAS)

AF:

0.00

AC:

AN:

4664

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9380

Middle Eastern (MID)

AF:

0.0106

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.000163

AC:

AN:

67510

Other (OTH)

AF:

0.000971

AC:

AN:

2060

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000549

Hom.:

Bravo

AF:

0.000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

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

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

.;T

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.91

D;D

M_CAP

Pathogenic

0.47

MetaRNN

Uncertain

0.55

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.9

.;H

PhyloP100

PrimateAI

Uncertain

0.73

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

GERP RS

5.0

Varity_R

0.54

gMVP

0.88

Mutation Taster

=37/63

disease causing

(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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NM_002901.4:c.274G>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over