dbSNP rs5241: CALCA:p.Ser76Arg (chr11-14968997-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

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 the same amino acid substitution has been previously reported as Likely benign in 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

Variant links:

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]

CALCA links:

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]

CALCB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
CALCA	NM_001741.3 link	c.228C>A	p.Ser76Arg	missense_variant, splice_region_variant	Exon 4 of 4	ENST00000331587.9	NP_001732.1	P01258-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CALCA	ENST00000331587.9 link	c.228C>A	p.Ser76Arg	missense_variant, splice_region_variant	Exon 4 of 4	1	NM_001741.3	ENSP00000331746.4		P01258-1

Frequencies

GnomAD3 genomes

AF:

0.0498

AC:

7570

AN:

152082

Hom.:

472

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0116

AC XY:

8394

AN XY:

726716

show subpopulations

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.:

AF XY:

0.0506

AC XY:

3765

AN XY:

74414

show subpopulations

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:

ALSPAC

AF:

0.00727

AC:

ESP6500AA

AF:

0.147

AC:

646

ESP6500EA

AF:

0.00908

AC:

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

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.24

T;T

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.39

.;T

M_CAP

Benign

0.030

MetaRNN

Benign

0.0015

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

L;L

PrimateAI

Benign

0.35

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over