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rs1801725

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 5P and 2B. PM1PM2PP2BP4_Moderate

The NM_000388.4(CASR):c.2956G>A(p.Ala986Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign 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. A986S) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

CASR
NM_000388.4 missense

Scores

4
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.23
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 3 ACMG points.

PM1
In a region_of_interest Disordered (size 20) in uniprot entity CASR_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_000388.4
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant where missense usually causes diseases, CASR
BP4
Computational evidence support a benign effect (MetaRNN=0.15316647).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CASRNM_000388.4 linkuse as main transcriptc.2956G>A p.Ala986Thr missense_variant 7/7 ENST00000639785.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CASRENST00000639785.2 linkuse as main transcriptc.2956G>A p.Ala986Thr missense_variant 7/71 NM_000388.4 P1P41180-1
CASRENST00000498619.4 linkuse as main transcriptc.2986G>A p.Ala996Thr missense_variant 7/71 P41180-2
CASRENST00000638421.1 linkuse as main transcriptc.2956G>A p.Ala986Thr missense_variant 7/75 P1P41180-1
CASRENST00000490131.7 linkuse as main transcriptc.2725G>A p.Ala909Thr missense_variant 5/55

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1461864
Hom.:
0
Cov.:
73
AF XY:
0.00000413
AC XY:
3
AN XY:
727226
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000450
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

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 testingInvitaeSep 01, 2023In 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 output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 1038090). This variant has not been reported in the literature in individuals affected with CASR-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 986 of the CASR protein (p.Ala986Thr). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.072
BayesDel_addAF
Benign
0.00098
T
BayesDel_noAF
Benign
-0.24
Cadd
Benign
16
Dann
Uncertain
1.0
DEOGEN2
Benign
0.33
T;T;.;.
Eigen
Benign
-0.12
Eigen_PC
Benign
0.0068
FATHMM_MKL
Uncertain
0.96
D
M_CAP
Uncertain
0.13
D
MetaRNN
Benign
0.15
T;T;T;T
MetaSVM
Uncertain
-0.023
T
MutationAssessor
Benign
1.8
L;L;.;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Benign
0.35
T
Polyphen
0.35
B;B;.;.
Vest4
0.096
MutPred
0.14
.;.;Gain of loop (P = 0.0435);.;
MVP
0.93
MPC
0.58
ClinPred
0.58
D
GERP RS
4.9
Varity_R
0.15
gMVP
0.33

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: rs1801725; hg19: chr3-122003757; API