rs1553768082

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP2PP3_Moderate

The ENST00000639785.2(CASR):​c.1382T>A​(p.Leu461Gln) 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L461P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

CASR
ENST00000639785.2 missense

Scores

11
6
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.92
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in ENST00000639785.2
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, 0.937

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CASRNM_000388.4 linkuse as main transcriptc.1382T>A p.Leu461Gln missense_variant 5/7 ENST00000639785.2 NP_000379.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CASRENST00000639785.2 linkuse as main transcriptc.1382T>A p.Leu461Gln missense_variant 5/71 NM_000388.4 ENSP00000491584 P1P41180-1
CASRENST00000498619.4 linkuse as main transcriptc.1382T>A p.Leu461Gln missense_variant 5/71 ENSP00000420194 P41180-2
CASRENST00000638421.1 linkuse as main transcriptc.1382T>A p.Leu461Gln missense_variant 5/75 ENSP00000492190 P1P41180-1
CASRENST00000490131.7 linkuse as main transcriptc.1378-6297T>A intron_variant 5 ENSP00000418685

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

CASR-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesNov 02, 2022The CASR c.1382T>A variant is predicted to result in the amino acid substitution p.Leu461Gln. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. A different amino acid substitution as this position (p.Leu461Gln) has been reported in two individuals with familial hypocalciuric hypercalcemia (Hannan et al 2012. PubMed ID: 22422767). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Autosomal dominant hypocalcemia 1;C1809471:Familial hypocalciuric hypercalcemia Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 15, 2017In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with CASR-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with glutamine at codon 461 of the CASR protein (p.Leu461Gln). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and glutamine. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.65
BayesDel_addAF
Pathogenic
0.41
D
BayesDel_noAF
Pathogenic
0.35
CADD
Uncertain
26
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.81
D;D;.
Eigen
Pathogenic
0.86
Eigen_PC
Pathogenic
0.84
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.87
.;D;D
M_CAP
Pathogenic
0.35
D
MetaRNN
Pathogenic
0.94
D;D;D
MetaSVM
Uncertain
0.63
D
MutationAssessor
Uncertain
2.7
M;M;M
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.81
D
PROVEAN
Uncertain
-3.6
.;.;D
REVEL
Pathogenic
0.92
Sift
Benign
0.050
.;.;D
Sift4G
Uncertain
0.020
.;.;D
Polyphen
1.0
D;D;.
Vest4
0.97
MutPred
0.79
Loss of glycosylation at K462 (P = 0.0941);Loss of glycosylation at K462 (P = 0.0941);Loss of glycosylation at K462 (P = 0.0941);
MVP
1.0
MPC
1.6
ClinPred
0.99
D
GERP RS
5.9
Varity_R
0.93
gMVP
0.82

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs1553768082; hg19: chr3-121994663; API