chr3-122262322-C-A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP2BP4

The NM_000388.4(CASR):​c.1287C>A​(p.His429Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,613,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. H429R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

CASR
NM_000388.4 missense

Scores

2
3
14

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: -0.541

Publications

2 publications found
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]
CASR Gene-Disease associations (from GenCC):
  • autosomal dominant hypocalcemia 1
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Illumina, ClinGen, Labcorp Genetics (formerly Invitae)
  • familial hypocalciuric hypercalcemia 1
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Illumina, Orphanet, Genomics England PanelApp
  • neonatal severe primary hyperparathyroidism
    Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)
  • autosomal dominant hypocalcemia
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • epilepsy, idiopathic generalized, susceptibility to, 8
    Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
  • epilepsy
    Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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 neonatal severe primary hyperparathyroidism, autosomal dominant hypocalcemia 1, familial hypocalciuric hypercalcemia 1, epilepsy, autosomal dominant hypocalcemia, epilepsy, idiopathic generalized, susceptibility to, 8.
BP4
Computational evidence support a benign effect (MetaRNN=0.3803619).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CASRNM_000388.4 linkc.1287C>A p.His429Gln 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.1287C>A p.His429Gln missense_variant Exon 4 of 7 1 NM_000388.4 ENSP00000491584.2 P41180-1
CASRENST00000498619.4 linkc.1287C>A p.His429Gln missense_variant Exon 4 of 7 1 ENSP00000420194.1 P41180-2
CASRENST00000638421.1 linkc.1287C>A p.His429Gln missense_variant Exon 4 of 7 5 ENSP00000492190.1 P41180-1
CASRENST00000490131.7 linkc.1287C>A p.His429Gln missense_variant Exon 3 of 5 5 ENSP00000418685.2 A0A1X7SBX3

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152184
Hom.:
0
Cov.:
32
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:
0.000193
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000119
AC:
3
AN:
251228
AF XY:
0.00000737
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000163
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000753
AC:
11
AN:
1461618
Hom.:
0
Cov.:
33
AF XY:
0.00000825
AC XY:
6
AN XY:
727134
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33476
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26134
East Asian (EAS)
AF:
0.000126
AC:
5
AN:
39700
South Asian (SAS)
AF:
0.0000116
AC:
1
AN:
86256
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53386
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
0.00000270
AC:
3
AN:
1111784
Other (OTH)
AF:
0.0000331
AC:
2
AN:
60392
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.480
Heterozygous variant carriers
0
1
2
3
4
5
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152302
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74468
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41564
American (AMR)
AF:
0.00
AC:
0
AN:
15300
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.000193
AC:
1
AN:
5182
South Asian (SAS)
AF:
0.000207
AC:
1
AN:
4830
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10608
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68032
Other (OTH)
AF:
0.00
AC:
0
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.650
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.0000247
AC:
3
Asia WGS
AF:
0.00115
AC:
4
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Nephrolithiasis/nephrocalcinosis Uncertain:1
Apr 25, 2023
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.H429Q variant (also known as c.1287C>A), located in coding exon 3 of the CASR gene, results from a C to A substitution at nucleotide position 1287. The histidine at codon 429 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Autosomal dominant hypocalcemia 1;C1809471:Familial hypocalciuric hypercalcemia Uncertain:1
Jun 28, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 429 of the CASR protein (p.His429Gln). This variant is present in population databases (rs746515147, gnomAD 0.02%). This missense change has been observed in individual(s) with hypoparathyroidism and/or primary hyperparathyroidism (PMID: 31433868, 35586626). ClinVar contains an entry for this variant (Variation ID: 463895). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In 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. -

Autosomal dominant hypocalcemia 1;C0342637:Familial hypocalciuric hypercalcemia 1;C1832615:Neonatal severe primary hyperparathyroidism;C2752062:Epilepsy, idiopathic generalized, susceptibility to, 8 Uncertain:1
Dec 29, 2023
Fulgent Genetics, Fulgent Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.29
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Benign
-0.26
CADD
Benign
0.057
DANN
Benign
0.87
DEOGEN2
Pathogenic
0.84
D;D;.;.
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.18
N
LIST_S2
Benign
0.75
.;T;T;T
M_CAP
Benign
0.036
D
MetaRNN
Benign
0.38
T;T;T;T
MetaSVM
Benign
-0.69
T
MutationAssessor
Benign
1.6
L;L;L;.
PhyloP100
-0.54
PrimateAI
Uncertain
0.75
T
PROVEAN
Pathogenic
-5.0
.;.;D;D
REVEL
Uncertain
0.44
Sift
Benign
0.080
.;.;T;T
Sift4G
Uncertain
0.053
.;.;T;T
Polyphen
0.24
B;B;.;.
Vest4
0.36, 0.36
MutPred
0.78
Loss of catalytic residue at L431 (P = 0.0865);Loss of catalytic residue at L431 (P = 0.0865);Loss of catalytic residue at L431 (P = 0.0865);Loss of catalytic residue at L431 (P = 0.0865);
MVP
0.69
MPC
0.71
ClinPred
0.11
T
GERP RS
-4.9
Varity_R
0.68
gMVP
0.54
Mutation Taster
=51/49
polymorphism

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

Other links and lift over

dbSNP: rs746515147; hg19: chr3-121981169; API