11-14967810-G-T

Position:

• chr11-14967810-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001033953.3(CALCA):​c.272C>A​(p.Thr91Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CALCA NM_001033953.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.25

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.87

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CALCA	NM_001033953.3	c.272C>A	p.Thr91Asn	missense_variant	4/5		NP_001029125.1
CALCA	NM_001378950.1	c.272C>A	p.Thr91Asn	missense_variant	4/5		NP_001365879.1
CALCA	NR_125898.2	n.560C>A		non_coding_transcript_exon_variant	5/6
CALCA	NR_166196.1	n.584C>A		non_coding_transcript_exon_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CALCA	ENST00000494746.1	n.1270C>A		non_coding_transcript_exon_variant	2/3	1
CALCA	ENST00000469608.5	c.*18C>A		3_prime_UTR_variant, NMD_transcript_variant	5/6	1		ENSP00000420618
CALCA	ENST00000486207.6	c.272C>A	p.Thr91Asn	missense_variant	4/5	5		ENSP00000417833	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2023

The c.272C>A (p.T91N) alteration is located in exon 4 (coding exon 3) of the CALCA gene. This alteration results from a C to A substitution at nucleotide position 272, causing the threonine (T) at amino acid position 91 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T;T
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.033
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	.;D
M_CAP	Benign	0.012	T
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Benign	-0.89	T
MutationAssessor	Pathogenic	3.2	M;M
MutationTaster	Benign	1.0	N;N;D
PROVEAN	Uncertain	-2.8	D;D
REVEL	Benign	0.23
Sift	Benign	0.032	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		0.99	D;D
Vest4		0.72
MutPred		0.71		Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);
MVP		0.11
ClinPred		0.76	D
GERP RS		0.74

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

Publications

LitVar

Other links and lift over

dbSNP: rs1376969693; hg19: chr11-14989356;