chr14-90397070-C-T

Variant names:

• chr14-90397070-C-T
• rs141007341
• NM_006888.6:c.-161C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_006888.6(CALM1):​c.-161C>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 0.00228 in 692,668 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0074 (16 hom., cov: 34)
  • Exomes 𝑓: 0.00083 (5 hom.)
• Consequence: CALM1 NM_006888.6 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.253
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 14

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P
• catecholaminergic polymorphic ventricular tachycardia 4

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 14-90397070-C-T is Benign according to our data. Variant chr14-90397070-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1219590.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00743 (1131/152166) while in subpopulation AFR AF = 0.0256 (1062/41534). AF 95% confidence interval is 0.0243. There are 16 homozygotes in GnomAd4. There are 534 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1131 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006888.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CALM1	NM_006888.6	MANE Select	c.-161C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	NP_008819.1	P0DP23
	CALM1	NM_006888.6	MANE Select	c.-161C>T		5_prime_UTR	Exon 1 of 6	NP_008819.1	P0DP23
	CALM1	NM_001363669.2		c.-106+412C>T		intron	N/A	NP_001350598.1	Q96HY3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CALM1	ENST00000356978.9	TSL:1 MANE Select	c.-161C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	ENSP00000349467.4	P0DP23
	CALM1	ENST00000356978.9	TSL:1 MANE Select	c.-161C>T		5_prime_UTR	Exon 1 of 6	ENSP00000349467.4	P0DP23
	CALM1	ENST00000971957.1		c.-161C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	ENSP00000642016.1

Frequencies

GnomAD3 genomes AF: 0.00739 AC: 1124 AN: 152048 Hom.: 16 Cov.: 34

Gnomad AFR AF: 0.0255

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000883

Gnomad OTH AF: 0.00573

GnomAD4 exome AF: 0.000834 AC: 451 AN: 540502 Hom.: 5 Cov.: 7 AF XY: 0.000649 AC XY: 187 AN XY: 288180

African (AFR) AF: 0.0254 AC: 355 AN: 13958

American (AMR) AF: 0.00154 AC: 37 AN: 24064

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15884

East Asian (EAS) AF: 0.00 AC: 0 AN: 31704

South Asian (SAS) AF: 0.00 AC: 0 AN: 52738

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34100

Middle Eastern (MID) AF: 0.00113 AC: 3 AN: 2664

European-Non Finnish (NFE) AF: 0.0000268 AC: 9 AN: 335944

Other (OTH) AF: 0.00160 AC: 47 AN: 29446

GnomAD4 genome AF: 0.00743 AC: 1131 AN: 152166 Hom.: 16 Cov.: 34 AF XY: 0.00718 AC XY: 534 AN XY: 74398

African (AFR) AF: 0.0256 AC: 1062 AN: 41534

American (AMR) AF: 0.00333 AC: 51 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000883 AC: 6 AN: 67964

Other (OTH) AF: 0.00567 AC: 12 AN: 2116

Alfa AF: 0.000598 Hom.: 0

Bravo AF: 0.00859

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	8.4
DANN	Benign	0.89
PhyloP100		-0.25
PromoterAI		-0.060	Neutral
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Mutation Taster		=300/0	polymorphism

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

Other links and lift over

dbSNP: rs141007341; hg19: chr14-90863414;