7-134933302-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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. 13/21 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

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20237657).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CALD1	NM_033138.4	c.533G>C	p.Arg178Thr	missense_variant	Exon 5 of 15	ENST00000361675.7	NP_149129.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CALD1	ENST00000361675.7	c.533G>C	p.Arg178Thr	missense_variant	Exon 5 of 15	1	NM_033138.4	ENSP00000354826.2

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000258

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 21, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.533G>C (p.R178T) alteration is located in exon 5 (coding exon 3) of the CALD1 gene. This alteration results from a G to C substitution at nucleotide position 533, causing the arginine (R) at amino acid position 178 to be replaced by a threonine (T). 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	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;.;T;.;.;.;T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	.;D;D;D;D;D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.20	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.4	M;.;M;M;M;.;.;.
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-2.2	N;N;N;N;N;N;D;N
REVEL	Benign	0.078
Sift	Uncertain	0.0080	D;D;D;D;D;D;D;D
Sift4G	Benign	0.12	T;T;T;T;T;T;D;T
Polyphen		0.062	B;.;.;B;B;B;B;.
Vest4		0.41
MutPred		0.48		Loss of MoRF binding (P = 0.0073);Loss of MoRF binding (P = 0.0073);Loss of MoRF binding (P = 0.0073);Loss of MoRF binding (P = 0.0073);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

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-134618053;