NM_001745.4:c.542C>A

Variant names:

• chr5-134741432-C-A
• rs1032082099
• NM_001745.4:c.542C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001745.4(CAMLG):​c.542C>A​(p.Thr181Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,524 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T181I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CAMLG NM_001745.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.38
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08659658).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001745.4. 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.542C>A	p.Thr181Lys	missense	Exon 2 of 4	NP_001736.1	P49069

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAMLG	ENST00000297156.4	TSL:1 MANE Select	c.542C>A	p.Thr181Lys	missense	Exon 2 of 4	ENSP00000297156.2	P49069
	CAMLG	ENST00000514518.1	TSL:1	c.173-2555C>A		intron	N/A	ENSP00000427331.1	D6RIW3
	CAMLG	ENST00000918602.1		c.593C>A	p.Thr198Lys	missense	Exon 3 of 5	ENSP00000588661.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461524 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727096

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111672

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.087	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		4.4
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.082
Sift	Benign	0.34	T
Sift4G	Benign	0.91	T
Polyphen		0.034	B
Vest4		0.18
MutPred		0.22		Gain of ubiquitination at T181 (P = 0.0054)
MVP		0.40
MPC		0.44
ClinPred		0.21	T
GERP RS		6.0
Varity_R		0.12
gMVP		0.25
Mutation Taster		=81/19	polymorphism

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

Other links and lift over

dbSNP: rs1032082099; hg19: chr5-134077122;