Genetic Variant CALM3:c.-14C>T (chr19-46601421-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_005184.4(CALM3):c.-14C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000148 in 1,352,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

CALM3
NM_005184.4 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.742

Publications

0 publications found

Variant links:

Genes affected

CALM3 (HGNC:1449): (calmodulin 3) This gene encodes a member of a family of proteins that binds calcium and functions as a enzymatic co-factor. Activity of this protein is important in the regulation of the cell cycle and cytokinesis. Multiple alternatively spliced transcript variants have been observed at this gene. [provided by RefSeq, Aug 2016]

CALM3 Gene-Disease associations (from GenCC):

familial long QT syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
long QT syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
long QT syndrome 16
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
catecholaminergic polymorphic ventricular tachycardia
Inheritance: AD Classification: MODERATE Submitted by: G2P, ClinGen

CALM3 links:

ENSG00000291145 (HGNC:):

ENSG00000291145 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005184.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CALM3	NM_005184.4	MANE Select	c.-14C>T	5_prime_UTR	Exon 1 of 6	NP_005175.2	P0DP25
CALM3	NM_001329924.2		c.-120C>T	5_prime_UTR	Exon 1 of 6	NP_001316853.1
CALM3	NM_001329925.2		c.-91C>T	5_prime_UTR	Exon 1 of 5	NP_001316854.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CALM3	ENST00000291295.14	TSL:1 MANE Select	c.-14C>T	5_prime_UTR	Exon 1 of 6	ENSP00000291295.8	P0DP25
CALM3	ENST00000866718.1		c.-14C>T	5_prime_UTR	Exon 1 of 6	ENSP00000536777.1
CALM3	ENST00000866714.1		c.-14C>T	5_prime_UTR	Exon 1 of 6	ENSP00000536773.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000148

AC:

AN:

1352808

Hom.:

Cov.:

AF XY:

0.00000150

AC XY:

AN XY:

667914

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

27896

American (AMR)

AF:

0.00

AC:

AN:

32282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23972

East Asian (EAS)

AF:

0.00

AC:

AN:

30580

South Asian (SAS)

AF:

0.0000130

AC:

AN:

77010

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39634

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4738

European-Non Finnish (NFE)

AF:

9.43e-7

AC:

AN:

1060822

Other (OTH)

AF:

0.00

AC:

AN:

55874

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.350

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Benign

0.87

PhyloP100

0.74

PromoterAI

-0.049

Neutral

(source)

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over