7-93426441-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 14/19 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3O:1

Conservation

PhyloP100: 1.29

Publications

58 publications found

Variant links:

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]

CALCR Gene-Disease associations (from GenCC):

osteoporosis
Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

CALCR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001742.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CALCR	NM_001742.4	MANE Select	c.1340T>C	p.Leu447Pro	missense	Exon 14 of 14	NP_001733.1
CALCR	NM_001164737.3		c.1388T>C	p.Leu463Pro	missense	Exon 16 of 16	NP_001158209.2
CALCR	NM_001164738.2		c.1340T>C	p.Leu447Pro	missense	Exon 13 of 13	NP_001158210.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CALCR	ENST00000426151.7	TSL:1 MANE Select	c.1340T>C	p.Leu447Pro	missense	Exon 14 of 14	ENSP00000389295.1
CALCR	ENST00000394441.5	TSL:1	c.1340T>C	p.Leu447Pro	missense	Exon 13 of 13	ENSP00000377959.1
CALCR	ENST00000415529.2	TSL:1	n.*565T>C		non_coding_transcript_exon	Exon 13 of 13	ENSP00000413179.1

Frequencies

GnomAD3 genomes

AF:

0.368

AC:

55853

AN:

151764

Hom.:

11927

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.386

AC:

97049

AN:

251462

AF XY:

0.379

show subpopulations

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 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.:

AF XY:

0.310

AC XY:

225437

AN XY:

726582

show subpopulations

African (AFR)

AF:

0.492

AC:

16440

AN:

33432

American (AMR)

AF:

0.500

AC:

22371

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.322

AC:

8405

AN:

26128

East Asian (EAS)

AF:

0.875

AC:

34751

AN:

39696

South Asian (SAS)

AF:

0.489

AC:

42128

AN:

86212

European-Finnish (FIN)

AF:

0.265

AC:

14148

AN:

53416

Middle Eastern (MID)

AF:

0.403

AC:

2323

AN:

5768

European-Non Finnish (NFE)

AF:

0.257

AC:

285541

AN:

1110668

Other (OTH)

AF:

0.348

AC:

20990

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

13773

27546

41320

55093

68866

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10128

20256

30384

40512

50640

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.368

AC:

55920

AN:

151882

Hom.:

11947

Cov.:

AF XY:

0.377

AC XY:

27990

AN XY:

74210

show subpopulations

African (AFR)

AF:

0.484

AC:

20044

AN:

41378

American (AMR)

AF:

0.426

AC:

6503

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.323

AC:

1122

AN:

3472

East Asian (EAS)

AF:

0.857

AC:

4373

AN:

5102

South Asian (SAS)

AF:

0.503

AC:

2427

AN:

4822

European-Finnish (FIN)

AF:

0.266

AC:

2798

AN:

10526

Middle Eastern (MID)

AF:

0.422

AC:

124

AN:

294

European-Non Finnish (NFE)

AF:

0.258

AC:

17515

AN:

67984

Other (OTH)

AF:

0.378

AC:

798

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1649

3298

4946

6595

8244

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

536

1072

1608

2144

2680

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.306

Hom.:

37091

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

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

CALCR-related disorder (1)

BONE MINERAL DENSITY QUANTITATIVE TRAIT LOCUS 15 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.040

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.69

CADD

Benign

(source)

DANN

Benign

0.036

DEOGEN2

Benign

0.0066

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.0029

LIST_S2

Benign

0.098

MetaRNN

Benign

9.3e-7

MetaSVM

Benign

-1.0

PhyloP100

1.3

PrimateAI

Benign

0.36

PROVEAN

Benign

1.8

REVEL

Benign

0.040

Sift

Benign

1.0

Sift4G

Benign

0.48

Vest4

0.023

MPC

0.30

ClinPred

0.00052

GERP RS

1.3

gMVP

0.28

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over