7-93426442-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001742.4(CALCR):c.1339C>A(p.Leu447Met) 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 benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L447P) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CALCR NM_001742.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.19

Genes affected

CALCR (HGNC:1440): (calcitonin receptor) This gene encodes a high affinity receptor for the peptide hormone calcitonin and belongs to a subfamily of seven transmembrane-spanning G protein-coupled receptors. The encoded protein is involved in maintaining calcium homeostasis and in regulating osteoclast-mediated bone resorption. Polymorphisms in this gene have been associated with variations in bone mineral density and onset of osteoporosis. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11454123).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CALCR	NM_001742.4	c.1339C>A	p.Leu447Met	missense_variant	14/14	ENST00000426151.7
CALCR	NM_001164737.3	c.1387C>A	p.Leu463Met	missense_variant	16/16
CALCR	NM_001164738.2	c.1339C>A	p.Leu447Met	missense_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CALCR	ENST00000426151.7	c.1339C>A	p.Leu447Met	missense_variant	14/14	1	NM_001742.4	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

Jun 23, 2023

The c.1339C>A (p.L447M) alteration is located in exon 14 (coding exon 12) of the CALCR gene. This alteration results from a C to A substitution at nucleotide position 1339, causing the leucine (L) at amino acid position 447 to be replaced by a methionine (M). 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
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	21
Dann	Uncertain	0.98
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.27	T;.;.;T;T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.11	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.36	N;N;N;.;N
REVEL	Benign	0.078
Sift	Benign	0.17	T;T;T;.;T
Sift4G	Benign	0.24	T;T;T;.;T
Vest4		0.070
MutPred		0.26		.;.;Loss of catalytic residue at L447 (P = 0.0341);.;Loss of catalytic residue at L447 (P = 0.0341);
MVP		0.40
MPC		0.42
ClinPred		0.31	T
GERP RS		4.2
gMVP		0.23

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-93055754;