chr14-90397063-C-T

Position:

• chr14-90397063-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_006888.6(CALM1):​c.-168C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00309 in 664,332 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0087 (23 hom., cov: 34)
  • Exomes 𝑓: 0.0014 (13 hom.)
• Consequence: CALM1 NM_006888.6 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.728

Genes affected

CALM1 (HGNC:1442): (calmodulin 1) This gene encodes one of three calmodulin proteins which are members of the EF-hand calcium-binding protein family. Calcium-induced activation of calmodulin regulates and modulates the function of cardiac ion channels. Two pseudogenes have been identified on chromosome 7 and X. Multiple transcript variants encoding different isoforms have been found for this gene.A missense mutation in the CALM1 gene has been associated with ventricular tachycardia.[provided by RefSeq, May 2020]

CALM1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 14-90397063-C-T is Benign according to our data. Variant chr14-90397063-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 679116.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00871 (1326/152218) while in subpopulation AFR AF= 0.0291 (1211/41556). AF 95% confidence interval is 0.0278. There are 23 homozygotes in gnomad4. There are 595 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1326 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CALM1	NM_006888.6	c.-168C>T		5_prime_UTR_premature_start_codon_gain_variant	1/6	ENST00000356978.9	NP_008819.1
CALM1	NM_006888.6	c.-168C>T		5_prime_UTR_variant	1/6	ENST00000356978.9	NP_008819.1
CALM1	NM_001363669.2	c.-106+405C>T		intron_variant			NP_001350598.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CALM1	ENST00000356978.9	c.-168C>T		5_prime_UTR_premature_start_codon_gain_variant	1/6	1	NM_006888.6	ENSP00000349467.4
CALM1	ENST00000356978.9	c.-168C>T		5_prime_UTR_variant	1/6	1	NM_006888.6	ENSP00000349467.4

Frequencies

GnomAD3 genomes AF: 0.00870 AC: 1323 AN: 152100 Hom.: 23 Cov.: 34

Gnomad AFR AF: 0.0292

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.00484

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00621

GnomAD4 exome AF: 0.00141 AC: 724 AN: 512114 Hom.: 13 Cov.: 6 AF XY: 0.00119 AC XY: 327 AN XY: 273826

Gnomad4 AFR exome AF: 0.0317

Gnomad4 AMR exome AF: 0.00249

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000318

Gnomad4 SAS exome AF: 0.000136

Gnomad4 FIN exome AF: 0.000300

Gnomad4 NFE exome AF: 0.000435

Gnomad4 OTH exome AF: 0.00267

GnomAD4 genome AF: 0.00871 AC: 1326 AN: 152218 Hom.: 23 Cov.: 34 AF XY: 0.00800 AC XY: 595 AN XY: 74418

Gnomad4 AFR AF: 0.0291

Gnomad4 AMR AF: 0.00484

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.0101

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	13
DANN	Benign	0.91
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1

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: rs146545930; hg19: chr14-90863407;