17-48849325-T-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005831.5(CALCOCO2):c.491T>A(p.Ile164Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,434 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CALCOCO2 NM_005831.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.247

Genes affected

CALCOCO2 (HGNC:29912): (calcium binding and coiled-coil domain 2) This gene encodes a coiled-coil domain-containing protein. The encoded protein functions as a receptor for ubiquitin-coated bacteria and plays an important role in innate immunity by mediating macroautophagy. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, May 2012]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.043887258).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CALCOCO2	NM_005831.5	c.491T>A	p.Ile164Asn	missense_variant	5/13	ENST00000258947.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CALCOCO2	ENST00000258947.8	c.491T>A	p.Ile164Asn	missense_variant	5/13	1	NM_005831.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461434 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727036

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 17, 2023

The c.491T>A (p.I164N) alteration is located in exon 5 (coding exon 4) of the CALCOCO2 gene. This alteration results from a T to A substitution at nucleotide position 491, causing the isoleucine (I) at amino acid position 164 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	Benign	0.066
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	16
Dann	Uncertain	0.98
DEOGEN2	Benign	0.0022	T;.;.;T;.;.;T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.083	N
LIST_S2	Benign	0.14	T;T;T;T;T;T;T
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.044	T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.69	N;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.51	N;N;N;N;N;N;N
REVEL	Benign	0.022
Sift	Uncertain	0.019	D;D;D;T;T;D;T
Sift4G	Benign	0.50	T;T;T;T;T;T;T
Polyphen		0.071	B;.;.;.;.;.;.
Vest4		0.11
MutPred		0.36		Loss of stability (P = 0.1321);.;.;.;.;.;Loss of stability (P = 0.1321);
MVP		0.22
MPC		0.50
ClinPred		0.085	T
GERP RS		-0.29
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.055
gMVP		0.13

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-46926687;