7-134867769-G-T

Variant names:

• chr7-134867769-G-T
• NM_033138.4:c.36G>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_033138.4(CALD1):​c.36G>T​(p.Arg12Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CALD1 NM_033138.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.27

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 4 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity CALD1_HUMAN
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CALD1	NM_033138.4	c.36G>T	p.Arg12Ser	missense_variant	Exon 3 of 15	ENST00000361675.7	NP_149129.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CALD1	ENST00000361675.7	c.36G>T	p.Arg12Ser	missense_variant	Exon 3 of 15	1	NM_033138.4	ENSP00000354826.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.36G>T (p.R12S) alteration is located in exon 3 (coding exon 1) of the CALD1 gene. This alteration results from a G to T substitution at nucleotide position 36, causing the arginine (R) at amino acid position 12 to be replaced by a serine (S). 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	1.0
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	22
DANN	Benign	0.86
DEOGEN2	Benign	0.29	.;T;.;T;D;.;.;T
Eigen	Benign	0.043
Eigen_PC	Benign	0.025
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.91	.;D;D;.;D;D;D;D
M_CAP	Benign	0.030	D
MetaRNN	Uncertain	0.59	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.97	L;.;L;.;L;L;.;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-2.4	N;N;N;D;D;N;D;D
REVEL	Uncertain	0.30
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.017	D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;D;D;.;.
Vest4		0.76
MutPred		0.54		Gain of phosphorylation at R12 (P = 2e-04);Gain of phosphorylation at R12 (P = 2e-04);Gain of phosphorylation at R12 (P = 2e-04);Gain of phosphorylation at R12 (P = 2e-04);Gain of phosphorylation at R12 (P = 2e-04);Gain of phosphorylation at R12 (P = 2e-04);Gain of phosphorylation at R12 (P = 2e-04);Gain of phosphorylation at R12 (P = 2e-04);
MVP		0.92
MPC		0.17
ClinPred		0.74	D
GERP RS		1.6
Varity_R		0.29
gMVP		0.10

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: chr7-134552520;