rs5241

Variant names:

• chr11-14968997-G-T
• rs5241
• NM_001741.3:c.228C>A

Variant summary

Our verdict is Benign. The variant received -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. 14/24 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.

• 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
• Publications: 18 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001741.3. 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
	CALCA	NM_001741.3	MANE Select	c.228C>A	p.Ser76Arg	missense splice_region	Exon 4 of 4	NP_001732.1	P01258-1
	CALCA	NM_001033952.3		c.228C>A	p.Ser76Arg	missense splice_region	Exon 4 of 4	NP_001029124.1	P01258-1
	CALCA	NM_001378949.1		c.228C>A	p.Ser76Arg	missense splice_region	Exon 5 of 5	NP_001365878.1	P01258-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CALCA	ENST00000331587.9	TSL:1 MANE Select	c.228C>A	p.Ser76Arg	missense splice_region	Exon 4 of 4	ENSP00000331746.4	P01258-1
	CALCA	ENST00000396372.2	TSL:1	c.228C>A	p.Ser76Arg	missense splice_region	Exon 4 of 4	ENSP00000379657.2	P01258-1
	CALCA	ENST00000469608.5	TSL:1	n.228C>A		splice_region non_coding_transcript_exon	Exon 4 of 6	ENSP00000420618.1	P01258-2

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

GnomAD2 exomes AF: 0.0207 AC: 5215 AN: 251334 AF XY: 0.0181

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 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

African (AFR) AF: 0.152 AC: 5086 AN: 33438

American (AMR) AF: 0.0117 AC: 522 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00394 AC: 103 AN: 26132

East Asian (EAS) AF: 0.0221 AC: 877 AN: 39698

South Asian (SAS) AF: 0.0153 AC: 1321 AN: 86210

European-Finnish (FIN) AF: 0.0310 AC: 1654 AN: 53414

Middle Eastern (MID) AF: 0.00851 AC: 43 AN: 5054

European-Non Finnish (NFE) AF: 0.00619 AC: 6884 AN: 1111808

Other (OTH) AF: 0.0170 AC: 1024 AN: 60316

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

African (AFR) AF: 0.149 AC: 6180 AN: 41496

American (AMR) AF: 0.0214 AC: 327 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3470

East Asian (EAS) AF: 0.0172 AC: 89 AN: 5174

South Asian (SAS) AF: 0.0156 AC: 75 AN: 4816

European-Finnish (FIN) AF: 0.0355 AC: 377 AN: 10606

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00654 AC: 445 AN: 68014

Other (OTH) AF: 0.0402 AC: 85 AN: 2112

Alfa AF: 0.0196 Hom.: 597

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 v4.9

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
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		6.9
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.070
Sift	Benign	0.12	T
Sift4G	Benign	0.47	T
Polyphen		0.59	P
Vest4		0.23
MutPred		0.19		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
Mutation Taster		=65/35	polymorphism (auto)

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

Other links and lift over

dbSNP: rs5241; hg19: chr11-14990543;