11-32097191-C-A

Variant names:

• chr11-32097191-C-A
• rs754621683
• NM_002901.4:c.302C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002901.4(RCN1):​c.302C>A​(p.Thr101Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T101I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RCN1 NM_002901.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.97
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002901.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RCN1	NM_002901.4	MANE Select	c.302C>A	p.Thr101Asn	missense	Exon 2 of 6	NP_002892.1	Q15293-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RCN1	ENST00000054950.4	TSL:1 MANE Select	c.302C>A	p.Thr101Asn	missense	Exon 2 of 6	ENSP00000054950.4	Q15293-1
	ENSG00000285283	ENST00000532942.5	TSL:2	c.149C>A	p.Thr50Asn	missense	Exon 2 of 6	ENSP00000436422.1
	ENSG00000285283	ENST00000530348.5	TSL:4	c.-197C>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 4	ENSP00000436482.1	E9PP27

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000139 AC: 2 AN: 1444026 Hom.: 0 Cov.: 35 AF XY: 0.00000139 AC XY: 1 AN XY: 717878

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000307 AC: 1 AN: 32582

American (AMR) AF: 0.00 AC: 0 AN: 40510

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25242

East Asian (EAS) AF: 0.00 AC: 0 AN: 39352

South Asian (SAS) AF: 0.00 AC: 0 AN: 82120

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53070

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5680

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1105948

Other (OTH) AF: 0.00 AC: 0 AN: 59522

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00666416), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.066	T
Eigen	Benign	-0.043
Eigen_PC	Benign	0.020
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.042	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		6.0
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.98	N
REVEL	Benign	0.097
Sift	Benign	0.47	T
Sift4G	Benign	0.41	T
Polyphen		0.015	B
Vest4		0.68
MutPred		0.32		Loss of phosphorylation at T101 (P = 0.0605)
MVP		0.74
MPC		0.64
ClinPred		0.83	D
GERP RS		4.1
Varity_R		0.26
gMVP		0.58
Mutation Taster		=41/59	disease causing

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

Other links and lift over

dbSNP: rs754621683; hg19: chr11-32118737;