Variant 3-122282161-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP2PP3PP5_Very_Strong

The NM_000388.4(CASR):c.1657G>A(p.Gly553Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Consequence

CASR
NM_000388.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 9.88

Variant links:

Genes affected

CASR (HGNC:1514): (calcium sensing receptor) The protein encoded by this gene is a plasma membrane G protein-coupled receptor that senses small changes in circulating calcium concentration. The encoded protein couples this information to intracellular signaling pathways that modify parathyroid hormone secretion or renal cation handling, and thus this protein plays an essential role in maintaining mineral ion homeostasis. Mutations in this gene are a cause of familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia. [provided by RefSeq, Aug 2017]

CASR links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a disulfide_bond (size 20) in uniprot entity CASR_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in NM_000388.4

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CASR. . Gene score misZ 3.1237 (greater than the threshold 3.09). Trascript score misZ 4.8257 (greater than threshold 3.09). GenCC has associacion of gene with epilepsy, autosomal dominant hypocalcemia, familial hypocalciuric hypercalcemia 1, epilepsy, idiopathic generalized, susceptibility to, 8, neonatal severe primary hyperparathyroidism, autosomal dominant hypocalcemia 1.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.836

PP5

Variant 3-122282161-G-A is Pathogenic according to our data. Variant chr3-122282161-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-122282161-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASR	NM_000388.4 linkuse as main transcript	c.1657G>A	p.Gly553Arg	missense_variant	6/7	ENST00000639785.2	NP_000379.3	P41180-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CASR	ENST00000639785.2 linkuse as main transcript	c.1657G>A	p.Gly553Arg	missense_variant	6/7	1	NM_000388.4	ENSP00000491584.2	P41180-1
CASR	ENST00000498619.4 linkuse as main transcript	c.1687G>A	p.Gly563Arg	missense_variant	6/7	1		ENSP00000420194.1	P41180-2
CASR	ENST00000638421.1 linkuse as main transcript	c.1657G>A	p.Gly553Arg	missense_variant	6/7	5		ENSP00000492190.1	P41180-1
CASR	ENST00000490131.7 linkuse as main transcript	c.1426G>A	p.Gly476Arg	missense_variant	4/5	5		ENSP00000418685.2	A0A1X7SBX3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial hypocalciuric hypercalcemia 1

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 29, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2007	- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.35

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.70

D;D;.;.

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

.;D;D;D

M_CAP

Uncertain

0.10

MetaRNN

Pathogenic

0.84

D;D;D;D

MetaSVM

Uncertain

0.56

MutationAssessor

Benign

1.1

L;L;.;.

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-3.8

.;.;D;.

REVEL

Pathogenic

0.72

Sift

Uncertain

0.0050

.;.;D;.

Sift4G

Uncertain

0.0080

.;.;D;.

Polyphen

1.0

D;D;.;.

Vest4

0.97

MutPred

0.49

.;.;Loss of glycosylation at K562 (P = 0.0526);.;

MVP

0.96

MPC

1.7

ClinPred

0.99

GERP RS

6.2

Varity_R

0.92

gMVP

0.95

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over