NM_033138.4:c.364G>A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_033138.4(CALD1):​c.364G>A​(p.Asp122Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00225 in 1,613,574 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0020 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0023 ( 3 hom. )

Consequence

CALD1
NM_033138.4 missense

Scores

3
8
8

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 8.96
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.010435581).
BP6
Variant 7-134933133-G-A is Benign according to our data. Variant chr7-134933133-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 717728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS2
High AC in GnomAd4 at 298 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CALD1NM_033138.4 linkc.364G>A p.Asp122Asn missense_variant Exon 5 of 15 ENST00000361675.7 NP_149129.2 Q05682-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CALD1ENST00000361675.7 linkc.364G>A p.Asp122Asn missense_variant Exon 5 of 15 1 NM_033138.4 ENSP00000354826.2 Q05682-1

Frequencies

GnomAD3 genomes
AF:
0.00197
AC:
298
AN:
151620
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.000388
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00283
Gnomad ASJ
AF:
0.00202
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000285
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00328
Gnomad OTH
AF:
0.00240
GnomAD3 exomes
AF:
0.00195
AC:
490
AN:
250832
Hom.:
1
AF XY:
0.00196
AC XY:
266
AN XY:
135660
show subpopulations
Gnomad AFR exome
AF:
0.000619
Gnomad AMR exome
AF:
0.00171
Gnomad ASJ exome
AF:
0.00159
Gnomad EAS exome
AF:
0.000163
Gnomad SAS exome
AF:
0.000131
Gnomad FIN exome
AF:
0.000878
Gnomad NFE exome
AF:
0.00327
Gnomad OTH exome
AF:
0.00131
GnomAD4 exome
AF:
0.00228
AC:
3333
AN:
1461836
Hom.:
3
Cov.:
32
AF XY:
0.00224
AC XY:
1628
AN XY:
727214
show subpopulations
Gnomad4 AFR exome
AF:
0.000299
Gnomad4 AMR exome
AF:
0.00188
Gnomad4 ASJ exome
AF:
0.00145
Gnomad4 EAS exome
AF:
0.000101
Gnomad4 SAS exome
AF:
0.000128
Gnomad4 FIN exome
AF:
0.000936
Gnomad4 NFE exome
AF:
0.00272
Gnomad4 OTH exome
AF:
0.00180
GnomAD4 genome
AF:
0.00196
AC:
298
AN:
151738
Hom.:
0
Cov.:
31
AF XY:
0.00197
AC XY:
146
AN XY:
74122
show subpopulations
Gnomad4 AFR
AF:
0.000387
Gnomad4 AMR
AF:
0.00283
Gnomad4 ASJ
AF:
0.00202
Gnomad4 EAS
AF:
0.000194
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000285
Gnomad4 NFE
AF:
0.00328
Gnomad4 OTH
AF:
0.00237
Alfa
AF:
0.00262
Hom.:
0
Bravo
AF:
0.00178
TwinsUK
AF:
0.00162
AC:
6
ALSPAC
AF:
0.00208
AC:
8
ESP6500AA
AF:
0.00113
AC:
5
ESP6500EA
AF:
0.00279
AC:
24
ExAC
AF:
0.00207
AC:
251
Asia WGS
AF:
0.000577
AC:
2
AN:
3478
EpiCase
AF:
0.00311
EpiControl
AF:
0.00231

ClinVar

Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
-
Breakthrough Genomics, Breakthrough Genomics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Dec 31, 2019
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.33
BayesDel_addAF
Benign
-0.35
T
BayesDel_noAF
Benign
-0.28
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.25
.;T;.;T;.;.;.;T
Eigen
Pathogenic
0.78
Eigen_PC
Pathogenic
0.74
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.95
.;D;D;D;D;D;D;D
M_CAP
Benign
0.031
D
MetaRNN
Benign
0.010
T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.52
T
MutationAssessor
Uncertain
2.7
M;.;M;M;M;.;.;.
PrimateAI
Uncertain
0.62
T
PROVEAN
Uncertain
-3.2
D;D;D;D;D;D;D;D
REVEL
Uncertain
0.36
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;D;D;.
Vest4
0.63
MVP
0.69
MPC
0.14
ClinPred
0.035
T
GERP RS
5.4
Varity_R
0.55
gMVP
0.16

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs140355865; hg19: chr7-134617884; COSMIC: COSV99054750; COSMIC: COSV99054750; API