NM_033138.4:c.512C>G

Variant names:

• chr7-134933281-C-G
• rs114442219
• NM_033138.4:c.512C>G

Variant summary

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

The NM_033138.4(CALD1):​c.512C>G​(p.Ser171Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. S171F) has been classified as Benign.

• Frequency: Genomes: not found (cov: 29)
• Consequence: CALD1 NM_033138.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.71
• Publications: 6 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 2 ACMG points.

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

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.512C>G	p.Ser171Cys	missense	Exon 5 of 15	NP_149129.2
	CALD1	NM_001438765.1		c.512C>G	p.Ser171Cys	missense	Exon 5 of 15	NP_001425694.1
	CALD1	NM_001438766.1		c.494C>G	p.Ser165Cys	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.512C>G	p.Ser171Cys	missense	Exon 5 of 15	ENSP00000354826.2	Q05682-1
	CALD1	ENST00000393118.7	TSL:1	c.494C>G	p.Ser165Cys	missense	Exon 3 of 13	ENSP00000376826.2	Q05682-3
	CALD1	ENST00000361901.6	TSL:1	c.512C>G	p.Ser171Cys	missense	Exon 5 of 14	ENSP00000354513.2	Q05682-4

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 29

Alfa AF: 0.00 Hom.: 39

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.0011	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.31	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		3.7
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.20
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.019	D
Polyphen		0.96	P
Vest4		0.48
MutPred		0.44		Gain of methylation at K170 (P = 0.0202)
MVP		0.38
MPC		0.14
ClinPred		0.98	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.29
gMVP		0.13
Mutation Taster		=71/29	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: rs114442219; hg19: chr7-134618032; COSMIC: COSV62654626; COSMIC: COSV62654626;