rs5241

chr11-14968997-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001741.3(CALCA):c.228C>A(p.Ser76Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0156 in 1,612,992 control chromosomes in the GnomAD database, including 996 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.050 (476 hom., cov: 32)
  • Exomes 𝑓: 0.012 (520 hom.)
• Consequence: CALCA NM_001741.3 missense, splice_region
• Scores: Splicing: ADA: 0.01387
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.91

Genes affected

CALCA (HGNC:1437): (calcitonin related polypeptide alpha) This gene encodes the peptide hormones calcitonin, calcitonin gene-related peptide and katacalcin by tissue-specific alternative RNA splicing of the gene transcripts and cleavage of inactive precursor proteins. Calcitonin is involved in calcium regulation and acts to regulate phosphorus metabolism. Calcitonin gene-related peptide functions as a vasodilator and as an antimicrobial peptide while katacalcin is a calcium-lowering peptide. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Aug 2014]

CALCB (HGNC:1438): (calcitonin related polypeptide beta) Predicted to enable calcitonin receptor binding activity. Predicted to be involved in adenylate cyclase-activating G protein-coupled receptor signaling pathway and regulation of cytosolic calcium ion concentration. Predicted to be located in extracellular region. Predicted to be active in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015355945).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.146 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CALCA	NM_001741.3	c.228C>A	p.Ser76Arg	missense_variant, splice_region_variant	4/4	ENST00000331587.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CALCA	ENST00000331587.9	c.228C>A	p.Ser76Arg	missense_variant, splice_region_variant	4/4	1	NM_001741.3

Frequencies

GnomAD3 genomes AF: 0.0498 AC: 7570 AN: 152082 Hom.: 472 Cov.: 32

Gnomad AFR AF: 0.149

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0214

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.0172

Gnomad SAS AF: 0.0158

Gnomad FIN AF: 0.0355

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00654

Gnomad OTH AF: 0.0407

GnomAD3 exomes AF: 0.0207 AC: 5215 AN: 251334 Hom.: 232 AF XY: 0.0181 AC XY: 2462 AN XY: 135852

Gnomad AFR exome AF: 0.154

Gnomad AMR exome AF: 0.0103

Gnomad ASJ exome AF: 0.00357

Gnomad EAS exome AF: 0.0165

Gnomad SAS exome AF: 0.0165

Gnomad FIN exome AF: 0.0302

Gnomad NFE exome AF: 0.00682

Gnomad OTH exome AF: 0.0122

GnomAD4 exome AF: 0.0120 AC: 17514 AN: 1460792 Hom.: 520 Cov.: 31 AF XY: 0.0116 AC XY: 8394 AN XY: 726716

Gnomad4 AFR exome AF: 0.152

Gnomad4 AMR exome AF: 0.0117

Gnomad4 ASJ exome AF: 0.00394

Gnomad4 EAS exome AF: 0.0221

Gnomad4 SAS exome AF: 0.0153

Gnomad4 FIN exome AF: 0.0310

Gnomad4 NFE exome AF: 0.00619

Gnomad4 OTH exome AF: 0.0170

GnomAD4 genome AF: 0.0499 AC: 7594 AN: 152200 Hom.: 476 Cov.: 32 AF XY: 0.0506 AC XY: 3765 AN XY: 74414

Gnomad4 AFR AF: 0.149

Gnomad4 AMR AF: 0.0214

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.0172

Gnomad4 SAS AF: 0.0156

Gnomad4 FIN AF: 0.0355

Gnomad4 NFE AF: 0.00654

Gnomad4 OTH AF: 0.0402

Alfa AF: 0.0130 Hom.: 153

Bravo AF: 0.0542

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.147 AC: 646

ESP6500EA AF: 0.00908 AC: 78

ExAC AF: 0.0234 AC: 2836

Asia WGS AF: 0.0290 AC: 102 AN: 3478

EpiCase AF: 0.00616

EpiControl AF: 0.00545

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.24	T;T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.0015	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.070
Sift	Benign	0.12	T;T
Sift4G	Benign	0.47	T;T
Polyphen		0.59	P;P
Vest4		0.23
MutPred		0.19		Loss of phosphorylation at S76 (P = 0.0131);Loss of phosphorylation at S76 (P = 0.0131);
MPC		0.20
ClinPred		0.020	T
GERP RS		3.8
Varity_R		0.12
gMVP		0.066

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.014
dbscSNV1_RF	Benign	0.16
SpliceAI score (max)		0.070		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: rs5241; hg19: chr11-14990543;