17-48849255-G-A

Variant names:

• chr17-48849255-G-A
• rs1177760303
• NM_005831.5:c.421G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005831.5(CALCOCO2):​c.421G>A​(p.Glu141Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,438 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CALCOCO2 NM_005831.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.95

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 Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CALCOCO2	NM_005831.5	c.421G>A	p.Glu141Lys	missense_variant	Exon 5 of 13	ENST00000258947.8	NP_005822.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CALCOCO2	ENST00000258947.8	c.421G>A	p.Glu141Lys	missense_variant	Exon 5 of 13	1	NM_005831.5	ENSP00000258947.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251234 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135762

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS 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: 0.00000274 AC: 4 AN: 1461438 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727032

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 31, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.421G>A (p.E141K) alteration is located in exon 5 (coding exon 4) of the CALCOCO2 gene. This alteration results from a G to A substitution at nucleotide position 421, causing the glutamic acid (E) at amino acid position 141 to be replaced by a lysine (K). 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	0.090
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0020	T;.;.;T;.;.;T;T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.86	D;D;D;T;D;D;T;D
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.097	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.63	N;.;.;.;.;.;.;.
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.68	N;N;N;N;N;N;N;N
REVEL	Benign	0.033
Sift	Benign	0.49	T;T;T;T;T;T;T;T
Sift4G	Benign	0.23	T;T;T;T;T;T;D;T
Polyphen		0.0080	B;.;.;.;.;.;.;.
Vest4		0.12
MutPred		0.46		Gain of methylation at E141 (P = 0.0037);.;.;.;.;.;.;Gain of methylation at E141 (P = 0.0037);
MVP		0.57
MPC		0.28
ClinPred		0.16	T
GERP RS		3.9
Varity_R		0.025
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.21		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1177760303; hg19: chr17-46926617; COSMIC: COSV51951457; COSMIC: COSV51951457;