Genetic Variant CALCOCO1:p.Arg557Leu (chr12-53713822-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_020898.3(CALCOCO1):c.1670G>T(p.Arg557Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000212 in 1,416,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 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. R557H) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CALCOCO1
NM_020898.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.35

Variant links:

Genes affected

CALCOCO1 (HGNC:29306): (calcium binding and coiled-coil domain 1) Enables several functions, including armadillo repeat domain binding activity; beta-catenin binding activity; and nuclear receptor coactivator activity. Involved in positive regulation of gene expression and positive regulation of transcription, DNA-templated. Located in cytosol and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

CALCOCO1 links:

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ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.062464654).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CALCOCO1	NM_020898.3 link	c.1670G>T	p.Arg557Leu	missense_variant	Exon 13 of 15	ENST00000550804.6	NP_065949.1	Q9P1Z2-1A0A024RAZ1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CALCOCO1	ENST00000550804.6 link	c.1670G>T	p.Arg557Leu	missense_variant	Exon 13 of 15	1	NM_020898.3	ENSP00000449960.1		Q9P1Z2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000212

AC:

AN:

1416600

Hom.:

Cov.:

AF XY:

0.00000285

AC XY:

AN XY:

702100

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31580

American (AMR)

AF:

0.00

AC:

AN:

36250

Ashkenazi Jewish (ASJ)

AF:

0.0000875

AC:

AN:

22852

East Asian (EAS)

AF:

0.00

AC:

AN:

39344

South Asian (SAS)

AF:

0.00

AC:

AN:

78656

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51878

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5522

European-Non Finnish (NFE)

AF:

9.16e-7

AC:

AN:

1092196

Other (OTH)

AF:

0.00

AC:

AN:

58322

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.64

CADD

Benign

0.0040

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.043

.;.;.;T

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.78

T;T;T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.062

T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.14

N;.;N;N

PhyloP100

-2.4

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.1

N;N;N;N

REVEL

Benign

0.019

Sift

Benign

0.032

D;T;T;T

Sift4G

Benign

0.42

T;T;T;T

Polyphen

0.047

B;.;B;B

Vest4

0.35

MutPred

0.42

Gain of catalytic residue at E556 (P = 0.0038);.;Gain of catalytic residue at E556 (P = 0.0038);Gain of catalytic residue at E556 (P = 0.0038);

MVP

0.081

MPC

0.28

ClinPred

0.081

GERP RS

-2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.036

gMVP

0.18

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

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