7-134933176-G-A

Position:

• chr7-134933176-G-A

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 543 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CALD1	NM_033138.4	c.407G>A	p.Arg136Lys	missense_variant	5/15	ENST00000361675.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CALD1	ENST00000361675.7	c.407G>A	p.Arg136Lys	missense_variant	5/15	1	NM_033138.4
	ENST00000665703.1	n.71+64907C>T		intron_variant, non_coding_transcript_variant

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

GnomAD3 exomes AF: 0.00630 AC: 1575 AN: 249930 Hom.: 22 AF XY: 0.00755 AC XY: 1021 AN XY: 135276

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 SAS exome AF: 0.0301

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

Gnomad4 AMR exome AF: 0.00103

Gnomad4 ASJ exome AF: 0.00356

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0289

Gnomad4 FIN exome AF: 0.00116

Gnomad4 NFE exome AF: 0.00465

Gnomad4 OTH exome AF: 0.00542

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

Gnomad4 AMR AF: 0.00251

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.000389

Gnomad4 SAS AF: 0.0286

Gnomad4 FIN AF: 0.000665

Gnomad4 NFE AF: 0.00449

Gnomad4 OTH AF: 0.00239

Alfa AF: 0.00423 Hom.: 3

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

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
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.75	D
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;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N
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

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;