chr7-93426412-C-T

Variant names:

• chr7-93426412-C-T
• rs147503225
• NM_001742.4:c.1369G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001742.4(CALCR):​c.1369G>A​(p.Glu457Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00326 in 1,613,848 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0020 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (11 hom.)
• Consequence: CALCR NM_001742.4 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.935
• Publications: 10 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0065184534).
• BP6: Variant 7-93426412-C-T is Benign according to our data. Variant chr7-93426412-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3043898.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAd4 at 2 Unknown gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CALCR	NM_001742.4	MANE Select	c.1369G>A	p.Glu457Lys	missense	Exon 14 of 14	NP_001733.1	P30988-2
	CALCR	NM_001164737.3		c.1417G>A	p.Glu473Lys	missense	Exon 16 of 16	NP_001158209.2	A0A0A0MSQ7
	CALCR	NM_001164738.2		c.1369G>A	p.Glu457Lys	missense	Exon 13 of 13	NP_001158210.1	P30988-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CALCR	ENST00000426151.7	TSL:1 MANE Select	c.1369G>A	p.Glu457Lys	missense	Exon 14 of 14	ENSP00000389295.1	P30988-2
	CALCR	ENST00000394441.5	TSL:1	c.1369G>A	p.Glu457Lys	missense	Exon 13 of 13	ENSP00000377959.1	P30988-2
	CALCR	ENST00000415529.2	TSL:1	n.*594G>A		non_coding_transcript_exon	Exon 13 of 13	ENSP00000413179.1	P30988-5

Frequencies

GnomAD3 genomes AF: 0.00202 AC: 308 AN: 152162 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00342

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00137 AC: 345 AN: 251488 AF XY: 0.00138

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000785

Gnomad NFE exome AF: 0.00236

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00339 AC: 4954 AN: 1461568 Hom.: 11 Cov.: 30 AF XY: 0.00324 AC XY: 2355 AN XY: 727122

African (AFR) AF: 0.000717 AC: 24 AN: 33468

American (AMR) AF: 0.00134 AC: 60 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86252

European-Finnish (FIN) AF: 0.000936 AC: 50 AN: 53418

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00410 AC: 4556 AN: 1111720

Other (OTH) AF: 0.00424 AC: 256 AN: 60386

GnomAD4 genome AF: 0.00202 AC: 308 AN: 152280 Hom.: 2 Cov.: 32 AF XY: 0.00138 AC XY: 103 AN XY: 74466

African (AFR) AF: 0.000770 AC: 32 AN: 41562

American (AMR) AF: 0.00196 AC: 30 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00342 AC: 233 AN: 68036

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.00243 Hom.: 1

Bravo AF: 0.00212

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00256 AC: 22

ExAC AF: 0.00105 AC: 127

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00305

EpiControl AF: 0.00279

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	CALCR-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	6.6
DANN	Benign	0.91
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.0065	T
MetaSVM	Benign	-1.1	T
PhyloP100		-0.94
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.18	N
REVEL	Benign	0.013
Sift	Benign	0.44	T
Sift4G	Benign	0.73	T
Vest4		0.092
MVP		0.26
MPC		0.28
ClinPred		0.0028	T
GERP RS		0.78
gMVP		0.37
Mutation Taster		=92/8	polymorphism

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: rs147503225; hg19: chr7-93055724; COSMIC: COSV64008692;