rs1553766282

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP2

The NM_000388.4(CASR):​c.463A>G​(p.Asn155Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

CASR
NM_000388.4 missense

Scores

1
8
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.21
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 Uncertain_significance. Variant got 5 ACMG points.

PM1
In a region_of_interest Ligand-binding 1 (LB1) (size 166) in uniprot entity CASR_HUMAN there are 70 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.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CASRNM_000388.4 linkuse as main transcriptc.463A>G p.Asn155Asp missense_variant 3/7 ENST00000639785.2 NP_000379.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CASRENST00000639785.2 linkuse as main transcriptc.463A>G p.Asn155Asp missense_variant 3/71 NM_000388.4 ENSP00000491584 P1P41180-1

Frequencies

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

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Autosomal dominant hypocalcemia 1;C1809471:Familial hypocalciuric hypercalcemia Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 14, 2019In 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 do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). 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 asparagine with aspartic acid at codon 155 of the CASR protein (p.Asn155Asp). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and aspartic acid. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.33
BayesDel_addAF
Uncertain
0.053
T
BayesDel_noAF
Benign
-0.16
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.48
T;T;.;.
Eigen
Benign
0.14
Eigen_PC
Uncertain
0.30
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.87
.;D;D;D
M_CAP
Benign
0.055
D
MetaRNN
Uncertain
0.50
D;D;D;D
MetaSVM
Benign
-0.29
T
MutationAssessor
Benign
1.6
L;L;L;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.74
T
PROVEAN
Benign
-2.0
.;.;N;N
REVEL
Uncertain
0.35
Sift
Benign
0.26
.;.;T;T
Sift4G
Benign
0.22
.;.;T;T
Polyphen
0.071
B;B;.;.
Vest4
0.41, 0.41
MutPred
0.56
Loss of glycosylation at S150 (P = 0.0323);Loss of glycosylation at S150 (P = 0.0323);Loss of glycosylation at S150 (P = 0.0323);Loss of glycosylation at S150 (P = 0.0323);
MVP
0.96
MPC
0.88
ClinPred
0.86
D
GERP RS
5.8
Varity_R
0.73
gMVP
0.92

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.

Other links and lift over

dbSNP: rs1553766282; hg19: chr3-121976205; API