Genetic Variant RCN1:p.Pro31His (chr11-32091288-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_002901.4(RCN1):c.92C>A(p.Pro31His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000117 in 1,544,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000057 ( 0 hom. )

Consequence

RCN1
NM_002901.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.51

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08139378).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RCN1	NM_002901.4 link	c.92C>A	p.Pro31His	missense_variant	Exon 1 of 6	ENST00000054950.4	NP_002892.1	Q15293-1V9HW95

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RCN1	ENST00000054950.4 link	c.92C>A	p.Pro31His	missense_variant	Exon 1 of 6	1	NM_002901.4	ENSP00000054950.4	Q15293-1
ENSG00000285283	ENST00000532942.5 link	c.102-5856C>A		intron_variant	Intron 1 of 5	2		ENSP00000436422.1
ENSG00000285283	ENST00000530348.5 link	c.-244-5856C>A		intron_variant	Intron 1 of 3	4		ENSP00000436482.1	E9PP27

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000685

AC:

AN:

145886

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000411

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000575

AC:

AN:

1391846

Hom.:

Cov.:

AF XY:

0.00000583

AC XY:

AN XY:

686234

show subpopulations

African (AFR)

AF:

0.0000646

AC:

AN:

30962

American (AMR)

AF:

0.0000564

AC:

AN:

35464

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25012

East Asian (EAS)

AF:

0.00

AC:

AN:

35470

South Asian (SAS)

AF:

0.00

AC:

AN:

78562

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48058

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4140

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1076580

Other (OTH)

AF:

0.0000694

AC:

AN:

57598

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152268

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41578

American (AMR)

AF:

0.000523

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67994

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000174

ExAC

AF:

0.0000173

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 06, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.92C>A (p.P31H) alteration is located in exon 1 (coding exon 1) of the RCN1 gene. This alteration results from a C to A substitution at nucleotide position 92, causing the proline (P) at amino acid position 31 to be replaced by a histidine (H). 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

0.74

BayesDel_addAF

Benign

-0.041

BayesDel_noAF

Benign

-0.17

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.71

M_CAP

Pathogenic

0.93

MetaRNN

Benign

0.081

MetaSVM

Benign

-0.75

MutationAssessor

Uncertain

2.3

PhyloP100

7.5

PrimateAI

Pathogenic

0.97

PROVEAN

Uncertain

-4.1

REVEL

Uncertain

0.40

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.011

Polyphen

1.0

Vest4

0.50

MutPred

0.44

Loss of glycosylation at T32 (P = 0.051);

MVP

0.65

MPC

1.5

ClinPred

0.99

GERP RS

3.7

PromoterAI

-0.092

Neutral

(source)

Varity_R

0.48

gMVP

0.78

Mutation Taster

=24/76

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

11-32091288-C-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