rs201328344
Positions:
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1PP2PP3BP6BS1
The NM_000388.4(CASR):c.2585T>C(p.Phe862Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000415 in 1,613,808 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).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000044 ( 0 hom. )
Consequence
CASR
NM_000388.4 missense
NM_000388.4 missense
Scores
6
6
2
Clinical Significance
Conservation
PhyloP100: 8.00
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_benign. Variant got -1 ACMG points.
PM1
?
In a transmembrane_region Helical; Name=7 (size 25) in uniprot entity CASR_HUMAN there are 12 pathogenic changes around while only 2 benign (86%) in NM_000388.4
PP2
?
Missense variant where missense usually causes diseases, CASR
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.775
BP6
?
Variant 3-122284539-T-C is Benign according to our data. Variant chr3-122284539-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 532619.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.
BS1
?
Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000445 (65/1461580) while in subpopulation SAS AF= 0.000672 (58/86258). AF 95% confidence interval is 0.000533. There are 0 homozygotes in gnomad4_exome. There are 48 alleles in male gnomad4_exome subpopulation. Median coverage is 70. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CASR | NM_000388.4 | c.2585T>C | p.Phe862Ser | missense_variant | 7/7 | ENST00000639785.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CASR | ENST00000639785.2 | c.2585T>C | p.Phe862Ser | missense_variant | 7/7 | 1 | NM_000388.4 | P1 | |
CASR | ENST00000498619.4 | c.2615T>C | p.Phe872Ser | missense_variant | 7/7 | 1 | |||
CASR | ENST00000638421.1 | c.2585T>C | p.Phe862Ser | missense_variant | 7/7 | 5 | P1 | ||
CASR | ENST00000490131.7 | c.2354T>C | p.Phe785Ser | missense_variant | 5/5 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152228Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000119 AC: 30AN: 251142Hom.: 0 AF XY: 0.000184 AC XY: 25AN XY: 135804
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GnomAD4 exome AF: 0.0000445 AC: 65AN: 1461580Hom.: 0 Cov.: 70 AF XY: 0.0000660 AC XY: 48AN XY: 727138
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152228Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74364
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Autosomal dominant hypocalcemia 1;C1809471:Familial hypocalciuric hypercalcemia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 06, 2023 | This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 862 of the CASR protein (p.Phe862Ser). This variant is present in population databases (rs201328344, gnomAD 0.09%). This variant has not been reported in the literature in individuals affected with CASR-related conditions. ClinVar contains an entry for this variant (Variation ID: 532619). 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. - |
Nephrolithiasis/nephrocalcinosis Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 24, 2024 | This alteration is classified as 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;.;.
Eigen
Uncertain
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;L;.;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
Polyphen
D;D;.;.
Vest4
0.76
MutPred
0.82
.;.;Gain of disorder (P = 0.0137);.;
MVP
0.95
MPC
1.3
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at