NM_016366.3:c.586G>A

Variant names:

• chr11-67519844-C-T
• rs199708887
• NM_016366.3:c.586G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_016366.3(CABP2):​c.586G>A​(p.Glu196Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,613,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: CABP2 NM_016366.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.39

Genes affected

CABP2 (HGNC:1385): (calcium binding protein 2) This gene belongs to a subfamily of calcium binding proteins that share similarity to calmodulin. Like calmodulin, these family members can likely stimulate calmodulin-dependent kinase II and the protein phosphatase calcineurin. Calcium binding proteins are an important component of calcium mediated cellular signal transduction. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.798

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CABP2	NM_016366.3	c.586G>A	p.Glu196Lys	missense_variant	Exon 6 of 7	ENST00000294288.5	NP_057450.2
CABP2	NM_001318496.2	c.604G>A	p.Glu202Lys	missense_variant	Exon 6 of 7		NP_001305425.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CABP2	ENST00000294288.5	c.586G>A	p.Glu196Lys	missense_variant	Exon 6 of 7	1	NM_016366.3	ENSP00000294288.4

Frequencies

GnomAD3 genomes AF: 0.0000525 AC: 8 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251214 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135810

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000260 AC: 38 AN: 1461716 Hom.: 0 Cov.: 32 AF XY: 0.0000289 AC XY: 21 AN XY: 727160

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.0000288

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152236 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74368

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000251 Hom.: 0

Bravo AF: 0.0000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Aug 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 196 of the CABP2 protein (p.Glu196Lys). This variant is present in population databases (rs199708887, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with CABP2-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.24	.;T;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.80	D;D;D
MetaSVM	Uncertain	-0.061	T
MutationAssessor	Benign	0.0050	.;N;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.3	D;D;.
REVEL	Uncertain	0.55
Sift	Uncertain	0.0010	D;D;.
Sift4G	Benign	0.16	T;T;.
Polyphen		1.0	D;D;.
Vest4		0.75
MVP		0.93
MPC		1.0
ClinPred		0.89	D
GERP RS		4.2
Varity_R		0.65
gMVP		0.86

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

LitVar

Other links and lift over

dbSNP: rs199708887; hg19: chr11-67287315; COSMIC: COSV53708671;