NM_033138.4:c.533G>C

Variant names:

• chr7-134933302-G-C
• rs558099957
• NM_033138.4:c.533G>C

Variant summary

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

The NM_033138.4(CALD1):​c.533G>C​(p.Arg178Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,453,628 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CALD1 NM_033138.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.47
• Publications: 0 publications found

Genes affected

CALD1 (HGNC:1441): (caldesmon 1) This gene encodes a calmodulin- and actin-binding protein that plays an essential role in the regulation of smooth muscle and nonmuscle contraction. The conserved domain of this protein possesses the binding activities to Ca(2+)-calmodulin, actin, tropomyosin, myosin, and phospholipids. This protein is a potent inhibitor of the actin-tropomyosin activated myosin MgATPase, and serves as a mediating factor for Ca(2+)-dependent inhibition of smooth muscle contraction. Alternative splicing of this gene results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2008]

ENSG00000286458 (HGNC:):

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=0.20237657).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033138.4. 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
	CALD1	NM_033138.4	MANE Select	c.533G>C	p.Arg178Thr	missense	Exon 5 of 15	NP_149129.2
	CALD1	NM_001438765.1		c.533G>C	p.Arg178Thr	missense	Exon 5 of 15	NP_001425694.1
	CALD1	NM_001438766.1		c.515G>C	p.Arg172Thr	missense	Exon 3 of 13	NP_001425695.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CALD1	ENST00000361675.7	TSL:1 MANE Select	c.533G>C	p.Arg178Thr	missense	Exon 5 of 15	ENSP00000354826.2	Q05682-1
	CALD1	ENST00000393118.7	TSL:1	c.515G>C	p.Arg172Thr	missense	Exon 3 of 13	ENSP00000376826.2	Q05682-3
	CALD1	ENST00000361901.6	TSL:1	c.533G>C	p.Arg178Thr	missense	Exon 5 of 14	ENSP00000354513.2	Q05682-4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1453628 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 722550

African (AFR) AF: 0.00 AC: 0 AN: 32866

American (AMR) AF: 0.00 AC: 0 AN: 44270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26066

East Asian (EAS) AF: 0.0000258 AC: 1 AN: 38794

South Asian (SAS) AF: 0.00 AC: 0 AN: 84606

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53106

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108076

Other (OTH) AF: 0.00 AC: 0 AN: 60078

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	19
DANN	Benign	0.88
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.5
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.078
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.12	T
Polyphen		0.062	B
Vest4		0.41
MutPred		0.48		Loss of MoRF binding (P = 0.0073)
MVP		0.47
MPC		0.22
ClinPred		0.69	D
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.080
gMVP		0.094
Mutation Taster		=87/13	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: rs558099957; hg19: chr7-134618053;