7-93426441-A-G

Position:

• chr7-93426441-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001742.4(CALCR):​c.1340T>C​(p.Leu447Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.312 in 1,612,250 control chromosomes in the GnomAD database, including 92,486 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L447M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.37 (11947 hom., cov: 32)
  • Exomes 𝑓: 0.31 (80539 hom.)
• Consequence: CALCR NM_001742.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: 1.29

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.341892E-7).
• BP6: Variant 7-93426441-A-G is Benign according to our data. Variant chr7-93426441-A-G is described in ClinVar as [Benign]. Clinvar id is 17636.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.836 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CALCR	NM_001742.4	c.1340T>C	p.Leu447Pro	missense_variant	14/14	ENST00000426151.7
CALCR	NM_001164737.3	c.1388T>C	p.Leu463Pro	missense_variant	16/16
CALCR	NM_001164738.2	c.1340T>C	p.Leu447Pro	missense_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CALCR	ENST00000426151.7	c.1340T>C	p.Leu447Pro	missense_variant	14/14	1	NM_001742.4	P1

Frequencies

GnomAD3 genomes AF: 0.368 AC: 55853 AN: 151764 Hom.: 11927 Cov.: 32

Gnomad AFR AF: 0.484

Gnomad AMI AF: 0.237

Gnomad AMR AF: 0.426

Gnomad ASJ AF: 0.323

Gnomad EAS AF: 0.857

Gnomad SAS AF: 0.505

Gnomad FIN AF: 0.266

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.258

Gnomad OTH AF: 0.377

GnomAD3 exomes AF: 0.386 AC: 97049 AN: 251462 Hom.: 22550 AF XY: 0.379 AC XY: 51556 AN XY: 135908

Gnomad AFR exome AF: 0.490

Gnomad AMR exome AF: 0.506

Gnomad ASJ exome AF: 0.325

Gnomad EAS exome AF: 0.860

Gnomad SAS exome AF: 0.487

Gnomad FIN exome AF: 0.267

Gnomad NFE exome AF: 0.261

Gnomad OTH exome AF: 0.342

GnomAD4 exome AF: 0.306 AC: 447097 AN: 1460368 Hom.: 80539 Cov.: 32 AF XY: 0.310 AC XY: 225437 AN XY: 726582

Gnomad4 AFR exome AF: 0.492

Gnomad4 AMR exome AF: 0.500

Gnomad4 ASJ exome AF: 0.322

Gnomad4 EAS exome AF: 0.875

Gnomad4 SAS exome AF: 0.489

Gnomad4 FIN exome AF: 0.265

Gnomad4 NFE exome AF: 0.257

Gnomad4 OTH exome AF: 0.348

GnomAD4 genome AF: 0.368 AC: 55920 AN: 151882 Hom.: 11947 Cov.: 32 AF XY: 0.377 AC XY: 27990 AN XY: 74210

Gnomad4 AFR AF: 0.484

Gnomad4 AMR AF: 0.426

Gnomad4 ASJ AF: 0.323

Gnomad4 EAS AF: 0.857

Gnomad4 SAS AF: 0.503

Gnomad4 FIN AF: 0.266

Gnomad4 NFE AF: 0.258

Gnomad4 OTH AF: 0.378

Alfa AF: 0.299 Hom.: 19119

Bravo AF: 0.388

TwinsUK AF: 0.260 AC: 963

ALSPAC AF: 0.258 AC: 993

ESP6500AA AF: 0.470 AC: 2073

ESP6500EA AF: 0.254 AC: 2187

ExAC AF: 0.380 AC: 46137

Asia WGS AF: 0.673 AC: 2338 AN: 3478

EpiCase AF: 0.262

EpiControl AF: 0.265

ClinVar

Significance: Benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	This variant is associated with the following publications: (PMID: 9675109) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

CALCR-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 18, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Bone mineral density quantitative trait locus 15 Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Dec 01, 1998

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.040
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	16
DANN	Benign	0.036
DEOGEN2	Benign	0.0066	.;T;T;T;T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.0029	N
LIST_S2	Benign	0.098	T;.;.;T;T
MetaRNN	Benign	9.3e-7	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.36	T
PROVEAN	Benign	1.8	N;N;N;.;N
REVEL	Benign	0.040
Sift	Benign	1.0	T;T;T;.;T
Sift4G	Benign	0.48	T;T;T;.;T
Vest4		0.023
MPC		0.30
ClinPred		0.00052	T
GERP RS		1.3
gMVP		0.28

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: rs1801197; hg19: chr7-93055753; COSMIC: COSV64008251;