3-122284215-A-G

Variant summary

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

The NM_000388.4(CASR):​c.2261A>G​(p.Gln754Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 33)
Exomes š‘“: 6.8e-7 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

CASR
NM_000388.4 missense

Scores

3
16

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.48
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1
In a topological_domain Extracellular (size 23) in uniprot entity CASR_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_000388.4
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the CASR gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 114 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 3.1237 (above the threshold of 3.09). Trascript score misZ: 4.8257 (above the threshold of 3.09). GenCC associations: The gene is linked to epilepsy, autosomal dominant hypocalcemia, familial hypocalciuric hypercalcemia 1, epilepsy, idiopathic generalized, susceptibility to, 8, neonatal severe primary hyperparathyroidism, autosomal dominant hypocalcemia 1.
BP4
Computational evidence support a benign effect (MetaRNN=0.2337141).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CASRNM_000388.4 linkc.2261A>G p.Gln754Arg missense_variant Exon 7 of 7 ENST00000639785.2 NP_000379.3 P41180-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CASRENST00000639785.2 linkc.2261A>G p.Gln754Arg missense_variant Exon 7 of 7 1 NM_000388.4 ENSP00000491584.2 P41180-1
CASRENST00000498619.4 linkc.2291A>G p.Gln764Arg missense_variant Exon 7 of 7 1 ENSP00000420194.1 P41180-2
CASRENST00000638421.1 linkc.2261A>G p.Gln754Arg missense_variant Exon 7 of 7 5 ENSP00000492190.1 P41180-1
CASRENST00000490131.7 linkc.2030A>G p.Gln677Arg missense_variant Exon 5 of 5 5 ENSP00000418685.2 A0A1X7SBX3

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152172
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250624
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135612
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000884
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
6.84e-7
AC:
1
AN:
1461752
Hom.:
0
Cov.:
70
AF XY:
0.00
AC XY:
0
AN XY:
727198
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152172
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74346
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000671
Hom.:
0
ExAC
AF:
0.00000824
AC:
1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.071
BayesDel_addAF
Benign
-0.025
T
BayesDel_noAF
Benign
-0.27
CADD
Benign
23
DANN
Benign
0.97
DEOGEN2
Benign
0.36
T;T;.;.
Eigen
Benign
-0.049
Eigen_PC
Benign
0.20
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.83
.;T;T;T
M_CAP
Benign
0.020
T
MetaRNN
Benign
0.23
T;T;T;T
MetaSVM
Benign
-0.59
T
MutationAssessor
Benign
0.34
N;N;.;.
PrimateAI
Uncertain
0.68
T
PROVEAN
Benign
-0.39
.;.;N;.
REVEL
Uncertain
0.30
Sift
Benign
0.36
.;.;T;.
Sift4G
Benign
0.35
.;.;T;.
Polyphen
0.024
B;B;.;.
Vest4
0.10
MutPred
0.50
.;.;Loss of glycosylation at S759 (P = 0.0236);.;
MVP
0.86
MPC
0.69
ClinPred
0.26
T
GERP RS
5.9
Varity_R
0.27
gMVP
0.52

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: rs777361297; hg19: chr3-122003062; API