3-122254374-G-T
Variant names:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP2PP3PP5
The NM_000388.4(CASR):c.185G>T(p.Arg62Met) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).
Frequency
Genomes: not found (cov: 32)
Consequence
CASR
NM_000388.4 missense, splice_region
NM_000388.4 missense, splice_region
Scores
9
4
5
Splicing: ADA: 0.9997
2
Clinical Significance
Conservation
PhyloP100: 9.92
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 Likely_pathogenic. Variant got 7 ACMG points.
PM1
In a region_of_interest Ligand-binding 1 (LB1) (size 166) in uniprot entity CASR_HUMAN there are 70 pathogenic changes around while only 0 benign (100%) 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.
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
PP5
Variant 3-122254374-G-T is Pathogenic according to our data. Variant chr3-122254374-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 8334.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-122254374-G-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Familial hypocalciuric hypercalcemia 1 Pathogenic:1
May 01, 1995
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only
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Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Benign
DEOGEN2
Uncertain
D;D;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
.;T;T;T
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Uncertain
D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
.;.;N;N
REVEL
Pathogenic
Sift
Benign
.;.;T;D
Sift4G
Benign
.;.;T;T
Polyphen
D;D;.;.
Vest4
0.77, 0.77
MutPred
Gain of catalytic residue at V58 (P = 0.0148);Gain of catalytic residue at V58 (P = 0.0148);Gain of catalytic residue at V58 (P = 0.0148);Gain of catalytic residue at V58 (P = 0.0148);
MVP
0.99
MPC
1.7
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 0
Find out detailed SpliceAI scores and Pangolin per-transcript scores at