12-53713822-C-T

Variant names:

• chr12-53713822-C-T
• rs748822880
• NM_020898.3:c.1670G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_020898.3(CALCOCO1):​c.1670G>A​(p.Arg557His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000121 in 1,568,920 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. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000099 (0 hom.)
• Consequence: CALCOCO1 NM_020898.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.35

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]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.029898107).
• BP6: Variant 12-53713822-C-T is Benign according to our data. Variant chr12-53713822-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2610133.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CALCOCO1	NM_020898.3	c.1670G>A	p.Arg557His	missense_variant	Exon 13 of 15	ENST00000550804.6	NP_065949.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CALCOCO1	ENST00000550804.6	c.1670G>A	p.Arg557His	missense_variant	Exon 13 of 15	1	NM_020898.3	ENSP00000449960.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000290 AC: 6 AN: 206700 AF XY: 0.0000181

Gnomad AFR exome AF: 0.000128

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000208

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000988 AC: 14 AN: 1416600 Hom.: 0 Cov.: 31 AF XY: 0.00000855 AC XY: 6 AN XY: 702100

African (AFR) AF: 0.000127 AC: 4 AN: 31580

American (AMR) AF: 0.00 AC: 0 AN: 36250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22852

East Asian (EAS) AF: 0.0000763 AC: 3 AN: 39344

South Asian (SAS) AF: 0.0000254 AC: 2 AN: 78656

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51878

Middle Eastern (MID) AF: 0.000181 AC: 1 AN: 5522

European-Non Finnish (NFE) AF: 0.00000275 AC: 3 AN: 1092196

Other (OTH) AF: 0.0000171 AC: 1 AN: 58322

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152320 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74474

African (AFR) AF: 0.0000962 AC: 4 AN: 41578

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jul 05, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.035
DANN	Benign	0.81
DEOGEN2	Benign	0.018	.;.;.;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0036	N
LIST_S2	Benign	0.62	T;T;T;T
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.030	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.20	N;.;N;N
PhyloP100		-2.4
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.24	N;N;N;N
REVEL	Benign	0.019
Sift	Benign	0.49	T;T;T;T
Sift4G	Benign	0.36	T;T;T;T
Polyphen		0.0010	B;.;B;B
Vest4		0.17
MutPred		0.41		Gain of catalytic residue at G558 (P = 2e-04);.;Gain of catalytic residue at G558 (P = 2e-04);Gain of catalytic residue at G558 (P = 2e-04);
MVP		0.030
MPC		0.23
ClinPred		0.013	T
GERP RS		-2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.011
gMVP		0.15
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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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Other links and lift over

dbSNP: rs748822880; hg19: chr12-54107606;