rs762998933

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_000388.4(CASR):​c.566A>C​(p.Asn189Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

CASR
NM_000388.4 missense

Scores

8
11

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.19
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.

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.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CASRNM_000388.4 linkc.566A>C p.Asn189Thr missense_variant Exon 4 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.566A>C p.Asn189Thr missense_variant Exon 4 of 7 1 NM_000388.4 ENSP00000491584.2 P41180-1
CASRENST00000498619.4 linkc.566A>C p.Asn189Thr missense_variant Exon 4 of 7 1 ENSP00000420194.1 P41180-2
CASRENST00000638421.1 linkc.566A>C p.Asn189Thr missense_variant Exon 4 of 7 5 ENSP00000492190.1 P41180-1
CASRENST00000490131.7 linkc.566A>C p.Asn189Thr missense_variant Exon 3 of 5 5 ENSP00000418685.2 A0A1X7SBX3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461862
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
727234
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:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.0054
T
BayesDel_noAF
Benign
-0.25
CADD
Benign
21
DANN
Uncertain
0.98
DEOGEN2
Benign
0.35
T;T;.;.
Eigen
Benign
0.052
Eigen_PC
Uncertain
0.24
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Uncertain
0.87
.;D;D;D
M_CAP
Benign
0.039
D
MetaRNN
Uncertain
0.54
D;D;D;D
MetaSVM
Uncertain
-0.26
T
MutationAssessor
Benign
0.56
N;N;N;.
PrimateAI
Uncertain
0.69
T
PROVEAN
Benign
-0.94
.;.;N;N
REVEL
Uncertain
0.32
Sift
Benign
0.13
.;.;T;T
Sift4G
Benign
0.16
.;.;T;T
Polyphen
0.061
B;B;.;.
Vest4
0.30, 0.29
MutPred
0.59
Loss of stability (P = 0.1334);Loss of stability (P = 0.1334);Loss of stability (P = 0.1334);Loss of stability (P = 0.1334);
MVP
0.80
MPC
0.66
ClinPred
0.58
D
GERP RS
5.8
Varity_R
0.43
gMVP
0.82

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-121980448; API