7-134933245-G-A

Position:

• chr7-134933245-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_033138.4(CALD1):​c.476G>A​(p.Arg159Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00217 in 1,608,310 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 29)
  • Exomes 𝑓: 0.0022 (9 hom.)
• Consequence: CALD1 NM_033138.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.69

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005922109).
• BS2: High AC in GnomAd4 at 292 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CALD1	NM_033138.4	c.476G>A	p.Arg159Lys	missense_variant	5/15	ENST00000361675.7	NP_149129.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CALD1	ENST00000361675.7	c.476G>A	p.Arg159Lys	missense_variant	5/15	1	NM_033138.4	ENSP00000354826
	ENST00000665703.1	n.71+64838C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00195 AC: 292 AN: 149972 Hom.: 1 Cov.: 29

Gnomad AFR AF: 0.000197

Gnomad AMI AF: 0.0475

Gnomad AMR AF: 0.000737

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000219

Gnomad FIN AF: 0.00164

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00311

Gnomad OTH AF: 0.000485

GnomAD3 exomes AF: 0.00129 AC: 315 AN: 243842 Hom.: 0 AF XY: 0.00126 AC XY: 166 AN XY: 132150

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.000644

Gnomad ASJ exome AF: 0.000404

Gnomad EAS exome AF: 0.0000560

Gnomad SAS exome AF: 0.0000339

Gnomad FIN exome AF: 0.00135

Gnomad NFE exome AF: 0.00227

Gnomad OTH exome AF: 0.00117

GnomAD4 exome AF: 0.00220 AC: 3205 AN: 1458220 Hom.: 9 Cov.: 33 AF XY: 0.00207 AC XY: 1498 AN XY: 725092

Gnomad4 AFR exome AF: 0.000181

Gnomad4 AMR exome AF: 0.000585

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.000164

Gnomad4 FIN exome AF: 0.00158

Gnomad4 NFE exome AF: 0.00269

Gnomad4 OTH exome AF: 0.00138

GnomAD4 genome AF: 0.00195 AC: 292 AN: 150090 Hom.: 1 Cov.: 29 AF XY: 0.00182 AC XY: 133 AN XY: 73096

Gnomad4 AFR AF: 0.000196

Gnomad4 AMR AF: 0.000736

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000219

Gnomad4 FIN AF: 0.00164

Gnomad4 NFE AF: 0.00311

Gnomad4 OTH AF: 0.000480

Alfa AF: 0.00242 Hom.: 1

Bravo AF: 0.00192

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00384 AC: 33

ExAC AF: 0.00127 AC: 154

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 22, 2022

The c.476G>A (p.R159K) alteration is located in exon 5 (coding exon 3) of the CALD1 gene. This alteration results from a G to A substitution at nucleotide position 476, causing the arginine (R) at amino acid position 159 to be replaced by a lysine (K). 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	0.082
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.22	.;T;.;T;.;.;.;T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.96	.;D;D;D;D;D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.0059	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.3	M;.;M;M;M;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.1	N;N;N;N;N;N;N;N
REVEL	Benign	0.17
Sift	Uncertain	0.018	D;D;D;D;D;D;D;D
Sift4G	Benign	0.30	T;T;T;T;T;T;T;T
Polyphen		0.14	B;.;.;B;B;B;B;.
Vest4		0.35
MVP		0.58
MPC		0.15
ClinPred		0.034	T
GERP RS		5.4
Varity_R		0.15
gMVP		0.078

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

LitVar

Other links and lift over

dbSNP: rs61755271; hg19: chr7-134617996;