5-134744021-C-A

Variant names:

• chr5-134744021-C-A
• rs777356231
• ENST00000514518.1:c.207C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000514518.1(CAMLG):​c.207C>A​(p.Cys69*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000775 in 1,291,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. C69C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: CAMLG ENST00000514518.1 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.57
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• congenital disorder of glycosylation, type IIz

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen, Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000514518.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAMLG	NM_001745.4	MANE Select	c.668C>A	p.Ala223Glu	missense	Exon 3 of 4	NP_001736.1	P49069

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAMLG	ENST00000514518.1	TSL:1	c.207C>A	p.Cys69*	stop_gained	Exon 2 of 3	ENSP00000427331.1	D6RIW3
	CAMLG	ENST00000297156.4	TSL:1 MANE Select	c.668C>A	p.Ala223Glu	missense	Exon 3 of 4	ENSP00000297156.2	P49069
	CAMLG	ENST00000918602.1		c.719C>A	p.Ala240Glu	missense	Exon 4 of 5	ENSP00000588661.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.75e-7 AC: 1 AN: 1291004 Hom.: 0 Cov.: 20 AF XY: 0.00000154 AC XY: 1 AN XY: 650536

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30002

American (AMR) AF: 0.00 AC: 0 AN: 43780

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24830

East Asian (EAS) AF: 0.00 AC: 0 AN: 38792

South Asian (SAS) AF: 0.00 AC: 0 AN: 81492

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52526

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5428

European-Non Finnish (NFE) AF: 0.00000104 AC: 1 AN: 959636

Other (OTH) AF: 0.00 AC: 0 AN: 54518

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	1.9	L
PhyloP100		5.6
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.59		Loss of helix (P = 0.0376)
MVP		0.47
MPC		1.0
ClinPred		0.98	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.89
gMVP		0.96
Mutation Taster		=63/137	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs777356231; hg19: chr5-134079711;