19-46601421-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005184.4(CALM3):c.-14C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.015 in 1,504,984 control chromosomes in the GnomAD database, including 227 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (17 hom., cov: 32)
  • Exomes 𝑓: 0.016 (210 hom.)
• Consequence: CALM3 NM_005184.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.742

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 19-46601421-C-A is Benign according to our data. Variant chr19-46601421-C-A is described in ClinVar as [Benign]. Clinvar id is 386525.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-46601421-C-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0107 (1630/152270) while in subpopulation NFE AF= 0.0169 (1151/67988). AF 95% confidence interval is 0.0161. There are 17 homozygotes in gnomad4. There are 699 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1630 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CALM3	NM_005184.4	c.-14C>A		5_prime_UTR_variant	1/6	ENST00000291295.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CALM3	ENST00000291295.14	c.-14C>A		5_prime_UTR_variant	1/6	1	NM_005184.4	P1

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1630 AN: 152152 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.00362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00667

Gnomad ASJ AF: 0.0334

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00566

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0169

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.0122 AC: 1238 AN: 101626 Hom.: 25 AF XY: 0.0120 AC XY: 682 AN XY: 57068

Gnomad AFR exome AF: 0.00237

Gnomad AMR exome AF: 0.00816

Gnomad ASJ exome AF: 0.0346

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00624

Gnomad FIN exome AF: 0.00374

Gnomad NFE exome AF: 0.0177

Gnomad OTH exome AF: 0.0167

GnomAD4 exome AF: 0.0155 AC: 20996 AN: 1352714 Hom.: 210 Cov.: 30 AF XY: 0.0154 AC XY: 10295 AN XY: 667880

Gnomad4 AFR exome AF: 0.00265

Gnomad4 AMR exome AF: 0.00802

Gnomad4 ASJ exome AF: 0.0363

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00587

Gnomad4 FIN exome AF: 0.00568

Gnomad4 NFE exome AF: 0.0171

Gnomad4 OTH exome AF: 0.0157

GnomAD4 genome AF: 0.0107 AC: 1630 AN: 152270 Hom.: 17 Cov.: 32 AF XY: 0.00939 AC XY: 699 AN XY: 74452

Gnomad4 AFR AF: 0.00361

Gnomad4 AMR AF: 0.00673

Gnomad4 ASJ AF: 0.0334

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00352

Gnomad4 FIN AF: 0.00566

Gnomad4 NFE AF: 0.0169

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.0169 Hom.: 15

Bravo AF: 0.0111

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 11, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 11, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 29, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
Cadd	Benign	18
Dann	Benign	0.77
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

LitVar

Other links and lift over

dbSNP: rs201296349; hg19: chr19-47104678;