3-122283867-G-A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 7P and 1B. PM1PM5PP2PP3_ModerateBP6

The NM_000388.4(CASR):​c.1913G>A​(p.Arg638His) variant causes a missense change. The variant allele was found at a frequency of 0.0000198 in 1,613,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R638L) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

CASR
NM_000388.4 missense

Scores

2
12
5

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 6.79

Publications

3 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: Likely_pathogenic. The variant received 6 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_000388.4
PM5
Other missense variant is known to change same aminoacid residue: Variant chr3-122283867-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 265466.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.854
BP6
Variant 3-122283867-G-A is Benign according to our data. Variant chr3-122283867-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 410330.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CASRNM_000388.4 linkc.1913G>A p.Arg638His 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.1913G>A p.Arg638His missense_variant Exon 7 of 7 1 NM_000388.4 ENSP00000491584.2 P41180-1
CASRENST00000498619.4 linkc.1943G>A p.Arg648His missense_variant Exon 7 of 7 1 ENSP00000420194.1 P41180-2
CASRENST00000638421.1 linkc.1913G>A p.Arg638His missense_variant Exon 7 of 7 5 ENSP00000492190.1 P41180-1
CASRENST00000490131.7 linkc.1682G>A p.Arg561His missense_variant Exon 5 of 5 5 ENSP00000418685.2 A0A1X7SBX3

Frequencies

GnomAD3 genomes
AF:
0.0000395
AC:
6
AN:
152002
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000358
AC:
9
AN:
251328
AF XY:
0.0000442
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.000173
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000465
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000178
AC:
26
AN:
1461682
Hom.:
0
Cov.:
33
AF XY:
0.0000124
AC XY:
9
AN XY:
727158
show subpopulations
African (AFR)
AF:
0.0000597
AC:
2
AN:
33478
American (AMR)
AF:
0.000157
AC:
7
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86254
European-Finnish (FIN)
AF:
0.0000188
AC:
1
AN:
53240
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000117
AC:
13
AN:
1111986
Other (OTH)
AF:
0.0000497
AC:
3
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.492
Heterozygous variant carriers
0
2
4
7
9
11
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:
0.0000394
AC:
6
AN:
152120
Hom.:
0
Cov.:
32
AF XY:
0.0000673
AC XY:
5
AN XY:
74342
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41484
American (AMR)
AF:
0.000131
AC:
2
AN:
15292
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5184
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4796
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10590
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.0000588
AC:
4
AN:
67986
Other (OTH)
AF:
0.00
AC:
0
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.508
Heterozygous variant carriers
0
1
1
2
2
3
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:
0.0000189
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

CASR-related disorder Uncertain:1
Sep 07, 2023
PreventionGenetics, part of Exact Sciences
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The CASR c.1943G>A variant is predicted to result in the amino acid substitution p.Arg648His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.017% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-122002714-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Autosomal dominant hypocalcemia 1;C0342637:Familial hypocalciuric hypercalcemia 1;C1832615:Neonatal severe primary hyperparathyroidism;C2752062:Epilepsy, idiopathic generalized, susceptibility to, 8 Uncertain:1
Jan 23, 2024
Fulgent Genetics, Fulgent Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Nephrolithiasis/nephrocalcinosis Benign:1
Feb 22, 2022
Ambry Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Autosomal dominant hypocalcemia 1;C1809471:Familial hypocalciuric hypercalcemia Benign:1
Oct 23, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Uncertain
0.039
T
BayesDel_noAF
Uncertain
0.070
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.79
D;D;.;.
Eigen
Uncertain
0.42
Eigen_PC
Uncertain
0.54
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.91
.;D;D;D
M_CAP
Uncertain
0.12
D
MetaRNN
Pathogenic
0.85
D;D;D;D
MetaSVM
Uncertain
0.38
D
MutationAssessor
Benign
1.6
L;L;.;.
PhyloP100
6.8
PrimateAI
Uncertain
0.77
T
PROVEAN
Uncertain
-3.4
.;.;D;.
REVEL
Uncertain
0.61
Sift
Benign
0.072
.;.;T;.
Sift4G
Benign
0.11
.;.;T;.
Polyphen
0.64
P;P;.;.
Vest4
0.31
MutPred
0.85
.;.;Gain of ubiquitination at K646 (P = 0.1111);.;
MVP
0.93
MPC
1.2
ClinPred
0.27
T
GERP RS
5.9
Varity_R
0.39
gMVP
0.94
Mutation Taster
=46/54
disease causing

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: rs201852643; hg19: chr3-122002714; COSMIC: COSV56140244; API