11-14971162-C-T

Variant names:

• chr11-14971162-C-T
• rs1555026441
• NM_001741.3:c.31G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001741.3(CALCA):​c.31G>A​(p.Ala11Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CALCA NM_001741.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.959
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2374489).

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.31G>A	p.Ala11Thr	missense	Exon 2 of 4	NP_001732.1	P01258-1
	CALCA	NM_001033952.3		c.31G>A	p.Ala11Thr	missense	Exon 2 of 4	NP_001029124.1	P01258-1
	CALCA	NM_001378949.1		c.31G>A	p.Ala11Thr	missense	Exon 3 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.31G>A	p.Ala11Thr	missense	Exon 2 of 4	ENSP00000331746.4	P01258-1
	CALCA	ENST00000396372.2	TSL:1	c.31G>A	p.Ala11Thr	missense	Exon 2 of 4	ENSP00000379657.2	P01258-1
	CALCA	ENST00000469608.5	TSL:1	n.31G>A		non_coding_transcript_exon	Exon 2 of 6	ENSP00000420618.1	P01258-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251482 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461840 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727208

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111970

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Benign	0.042
Eigen_PC	Benign	-0.039
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		0.96
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.079
Sift	Benign	0.077	T
Sift4G	Benign	0.24	T
Polyphen		0.96	D
Vest4		0.35
MutPred		0.27		Loss of stability (P = 0.137)
MVP		0.12
MPC		0.072
ClinPred		0.92	D
GERP RS		1.7
PromoterAI		0.0091	Neutral
Varity_R		0.050
gMVP		0.24
Mutation Taster		=87/13	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: rs1555026441; hg19: chr11-14992708;