7-134933176-G-A

Variant names:

• chr7-134933176-G-A
• rs75358773
• NM_033138.4:c.407G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_033138.4(CALD1):​c.407G>A​(p.Arg136Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00545 in 1,612,926 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0036 (7 hom., cov: 31)
  • Exomes 𝑓: 0.0056 (80 hom.)
• Consequence: CALD1 NM_033138.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.02

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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032838583).
• BP6: Variant 7-134933176-G-A is Benign according to our data. Variant chr7-134933176-G-A is described in ClinVar as [Benign]. Clinvar id is 770376.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00359 (543/151388) while in subpopulation SAS AF = 0.0286 (135/4718). AF 95% confidence interval is 0.0247. There are 7 homozygotes in GnomAd4. There are 277 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position FAILED quality control check.
• BS2: High AC in GnomAd4 at 543 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CALD1	NM_033138.4	c.407G>A	p.Arg136Lys	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.407G>A	p.Arg136Lys	missense_variant	Exon 5 of 15	1	NM_033138.4	ENSP00000354826.2

Frequencies

GnomAD3 genomes AF: 0.00358 AC: 541 AN: 151270 Hom.: 7 Cov.: 31

Gnomad AFR AF: 0.000998

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00251

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000388

Gnomad SAS AF: 0.0282

Gnomad FIN AF: 0.000665

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00449

Gnomad OTH AF: 0.00241

GnomAD2 exomes AF: 0.00630 AC: 1575 AN: 249930 AF XY: 0.00755

Gnomad AFR exome AF: 0.00212

Gnomad AMR exome AF: 0.000784

Gnomad ASJ exome AF: 0.00380

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00457

Gnomad OTH exome AF: 0.00443

GnomAD4 exome AF: 0.00564 AC: 8243 AN: 1461538 Hom.: 80 Cov.: 32 AF XY: 0.00634 AC XY: 4611 AN XY: 727074

Gnomad4 AFR exome AF: 0.00117 AC: 39 AN: 33458

Gnomad4 AMR exome AF: 0.00103 AC: 46 AN: 44648

Gnomad4 ASJ exome AF: 0.00356 AC: 93 AN: 26126

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39700

Gnomad4 SAS exome AF: 0.0289 AC: 2490 AN: 86202

Gnomad4 FIN exome AF: 0.00116 AC: 62 AN: 53374

Gnomad4 NFE exome AF: 0.00465 AC: 5166 AN: 1111888

Gnomad4 Remaining exome AF: 0.00542 AC: 327 AN: 60376

GnomAD4 genome AF: 0.00359 AC: 543 AN: 151388 Hom.: 7 Cov.: 31 AF XY: 0.00375 AC XY: 277 AN XY: 73914

Gnomad4 AFR AF: 0.000995 AC: 0.000994952 AN: 0.000994952

Gnomad4 AMR AF: 0.00251 AC: 0.00250991 AN: 0.00250991

Gnomad4 ASJ AF: 0.00288 AC: 0.00288184 AN: 0.00288184

Gnomad4 EAS AF: 0.000389 AC: 0.0003885 AN: 0.0003885

Gnomad4 SAS AF: 0.0286 AC: 0.0286138 AN: 0.0286138

Gnomad4 FIN AF: 0.000665 AC: 0.000665399 AN: 0.000665399

Gnomad4 NFE AF: 0.00449 AC: 0.00449269 AN: 0.00449269

Gnomad4 OTH AF: 0.00239 AC: 0.00238777 AN: 0.00238777

Alfa AF: 0.00430 Hom.: 5

Bravo AF: 0.00280

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00640 AC: 55

ExAC AF: 0.00704 AC: 855

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.00420

EpiControl AF: 0.00415

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	17
DANN	Benign	0.94
DEOGEN2	Benign	0.12	.;T;.;T;.;.;.;T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.80	.;T;T;T;T;T;T;T
MetaRNN	Benign	0.0033	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.3	M;.;M;M;M;.;.;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.1	N;N;N;N;N;N;N;N
REVEL	Benign	0.16
Sift	Benign	0.097	T;T;T;D;T;T;T;T
Sift4G	Benign	0.40	T;T;T;T;T;T;T;T
Polyphen		0.0030	B;.;.;B;B;B;B;.
Vest4		0.26
MVP		0.61
MPC		0.15
ClinPred		0.025	T
GERP RS		5.4
Varity_R		0.18
gMVP		0.056
Mutation Taster		=90/10	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

Publications

LitVar

Other links and lift over

dbSNP: rs75358773; hg19: chr7-134617927;