Genetic Variant CAMLG:p.Ala223Val (chr5-134744021-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001745.4(CAMLG):c.668C>T(p.Ala223Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000852 in 1,291,006 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000085 ( 0 hom. )

Consequence

CAMLG
NM_001745.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.57

Variant links:

Genes affected

CAMLG (HGNC:1471): (calcium modulating ligand) The immunosuppressant drug cyclosporin A blocks a calcium-dependent signal from the T-cell receptor (TCR) that normally leads to T-cell activation. When bound to cyclophilin B, cyclosporin A binds and inactivates the key signaling intermediate calcineurin. The protein encoded by this gene functions similarly to cyclosporin A, binding to cyclophilin B and acting downstream of the TCR and upstream of calcineurin by causing an influx of calcium. This integral membrane protein appears to be a new participant in the calcium signal transduction pathway, implicating cyclophilin B in calcium signaling, even in the absence of cyclosporin. [provided by RefSeq, Jul 2008]

CAMLG links:

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ACMG classification

Classification made for transcript

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
CAMLG	NM_001745.4 link	c.668C>T	p.Ala223Val	missense_variant	Exon 3 of 4	ENST00000297156.4	NP_001736.1	P49069
CAMLG	XM_047417791.1 link	c.633+2498C>T		intron_variant	Intron 2 of 2		XP_047273747.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAMLG	ENST00000297156.4 link	c.668C>T	p.Ala223Val	missense_variant	Exon 3 of 4	1	NM_001745.4	ENSP00000297156.2		P49069

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000208

AC:

AN:

240056

Hom.:

AF XY:

0.0000231

AC XY:

AN XY:

129724

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000550

Gnomad SAS exome

AF:

0.0000685

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000186

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000852

AC:

AN:

1291006

Hom.:

Cov.:

AF XY:

0.00000922

AC XY:

AN XY:

650538

show subpopulations

Gnomad4 AFR exome

AF:

0.000100

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000368

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000521

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 13, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.668C>T (p.A223V) alteration is located in exon 3 (coding exon 3) of the CAMLG gene. This alteration results from a C to T substitution at nucleotide position 668, causing the alanine (A) at amino acid position 223 to be replaced by a valine (V). 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

Pathogenic

0.93

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

0.10

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.016

MetaRNN

Uncertain

0.64

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.2

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-3.2

REVEL

Uncertain

0.30

Sift

Uncertain

0.0040

Sift4G

Benign

0.13

Polyphen

0.97

Vest4

0.71

MutPred

0.50

Loss of helix (P = 0.079);

MVP

0.41

MPC

0.32

ClinPred

0.67

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.66

gMVP

0.79

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over