7-93486987-A-G

Variant names:

• chr7-93486987-A-G
• rs2301680
• NM_001742.4:c.-6T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001742.4(CALCR):​c.-6T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.506 in 1,585,456 control chromosomes in the GnomAD database, including 205,725 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (21466 hom., cov: 32)
  • Exomes 𝑓: 0.50 (184259 hom.)
• Consequence: CALCR NM_001742.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.180
• Publications: 34 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.6090622E-6).
• BP6: Variant 7-93486987-A-G is Benign according to our data. Variant chr7-93486987-A-G is described in ClinVar as Benign. ClinVar VariationId is 1274950.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.672 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CALCR	NM_001742.4	MANE Select	c.-6T>C		5_prime_UTR	Exon 3 of 14	NP_001733.1
	CALCR	NM_001164737.3		c.-6T>C		5_prime_UTR	Exon 4 of 16	NP_001158209.2
	CALCR	NM_001164738.2		c.-6T>C		5_prime_UTR	Exon 2 of 13	NP_001158210.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CALCR	ENST00000426151.7	TSL:1 MANE Select	c.-6T>C		5_prime_UTR	Exon 3 of 14	ENSP00000389295.1
	CALCR	ENST00000394441.5	TSL:1	c.-6T>C		5_prime_UTR	Exon 2 of 13	ENSP00000377959.1
	CALCR	ENST00000649521.1		c.-6T>C		5_prime_UTR	Exon 3 of 15	ENSP00000497687.1

Frequencies

GnomAD3 genomes AF: 0.529 AC: 79976 AN: 151168 Hom.: 21443 Cov.: 32

Gnomad AFR AF: 0.608

Gnomad AMI AF: 0.554

Gnomad AMR AF: 0.437

Gnomad ASJ AF: 0.528

Gnomad EAS AF: 0.691

Gnomad SAS AF: 0.580

Gnomad FIN AF: 0.453

Gnomad MID AF: 0.541

Gnomad NFE AF: 0.497

Gnomad OTH AF: 0.531

GnomAD2 exomes AF: 0.504 AC: 123356 AN: 244898 AF XY: 0.510

Gnomad AFR exome AF: 0.609

Gnomad AMR exome AF: 0.348

Gnomad ASJ exome AF: 0.518

Gnomad EAS exome AF: 0.676

Gnomad FIN exome AF: 0.448

Gnomad NFE exome AF: 0.501

Gnomad OTH exome AF: 0.504

GnomAD4 exome AF: 0.503 AC: 721550 AN: 1434170 Hom.: 184259 Cov.: 27 AF XY: 0.506 AC XY: 361439 AN XY: 714500

African (AFR) AF: 0.609 AC: 19709 AN: 32356

American (AMR) AF: 0.362 AC: 15869 AN: 43786

Ashkenazi Jewish (ASJ) AF: 0.518 AC: 13350 AN: 25756

East Asian (EAS) AF: 0.675 AC: 26509 AN: 39248

South Asian (SAS) AF: 0.568 AC: 47779 AN: 84184

European-Finnish (FIN) AF: 0.444 AC: 23573 AN: 53130

Middle Eastern (MID) AF: 0.582 AC: 3287 AN: 5650

European-Non Finnish (NFE) AF: 0.496 AC: 540953 AN: 1090732

Other (OTH) AF: 0.514 AC: 30521 AN: 59328

GnomAD4 genome AF: 0.529 AC: 80041 AN: 151286 Hom.: 21466 Cov.: 32 AF XY: 0.525 AC XY: 38833 AN XY: 73920

African (AFR) AF: 0.608 AC: 25152 AN: 41368

American (AMR) AF: 0.436 AC: 6623 AN: 15176

Ashkenazi Jewish (ASJ) AF: 0.528 AC: 1825 AN: 3456

East Asian (EAS) AF: 0.691 AC: 3522 AN: 5096

South Asian (SAS) AF: 0.581 AC: 2800 AN: 4822

European-Finnish (FIN) AF: 0.453 AC: 4788 AN: 10578

Middle Eastern (MID) AF: 0.534 AC: 157 AN: 294

European-Non Finnish (NFE) AF: 0.497 AC: 33546 AN: 67484

Other (OTH) AF: 0.535 AC: 1123 AN: 2100

Alfa AF: 0.511 Hom.: 81913

Bravo AF: 0.528

TwinsUK AF: 0.516 AC: 1915

ALSPAC AF: 0.487 AC: 1878

ESP6500AA AF: 0.608 AC: 2677

ESP6500EA AF: 0.505 AC: 4341

ExAC AF: 0.517 AC: 62666

Asia WGS AF: 0.605 AC: 2104 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Apr 20, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 30389748)

CALCR-related disorder Benign:1

Oct 21, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	3.1
DANN	Benign	0.74
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.00039	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	0.0000016	T
MetaSVM	Benign	-0.94	T
PhyloP100		-0.18
PROVEAN	Benign	0.77	N
REVEL	Benign	0.050
Sift	Benign	1.0	T
Sift4G	Benign	0.35	T
Vest4		0.017
MPC		0.23
ClinPred		0.0019	T
GERP RS		0.093
gMVP		0.17
Mutation Taster		=298/2	polymorphism (auto)

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: rs2301680; hg19: chr7-93116299; COSMIC: COSV64006369; COSMIC: COSV64006369;