rs142704083
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS1
The NM_000388.4(CASR):c.3091G>A(p.Gly1031Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 1,614,220 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign 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. G1031D) has been classified as Uncertain significance.
Frequency
Consequence
NM_000388.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CASR | NM_000388.4 | c.3091G>A | p.Gly1031Ser | missense_variant | 7/7 | ENST00000639785.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CASR | ENST00000639785.2 | c.3091G>A | p.Gly1031Ser | missense_variant | 7/7 | 1 | NM_000388.4 | P1 | |
CASR | ENST00000498619.4 | c.3121G>A | p.Gly1041Ser | missense_variant | 7/7 | 1 | |||
CASR | ENST00000638421.1 | c.3091G>A | p.Gly1031Ser | missense_variant | 7/7 | 5 | P1 | ||
CASR | ENST00000490131.7 | c.2860G>A | p.Gly954Ser | missense_variant | 5/5 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000572 AC: 87AN: 152208Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000179 AC: 45AN: 251382Hom.: 1 AF XY: 0.000110 AC XY: 15AN XY: 135916
GnomAD4 exome AF: 0.0000561 AC: 82AN: 1461894Hom.: 1 Cov.: 37 AF XY: 0.0000454 AC XY: 33AN XY: 727248
GnomAD4 genome ? AF: 0.000571 AC: 87AN: 152326Hom.: 0 Cov.: 32 AF XY: 0.000550 AC XY: 41AN XY: 74496
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 13, 2019 | Variant summary: CASR c.3091G>A (p.Gly1031Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function (ACMG BP4). The variant allele was found at a frequency of 0.00022 in 277196 control chromosomes, predominantly at a frequency of 0.0022 within the African subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within African control individuals in the gnomAD database is approximately 176 fold of the estimated maximal expected allele frequency for a pathogenic variant in CASR causing Familial Hypocalciuric Hypercalcemia phenotype (1.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin (ACMG BS1). To our knowledge, no occurrence of c.3091G>A in individuals affected with Familial Hypocalciuric Hypercalcemia and no experimental evidence demonstrating its impact on protein function have been reported. This variant was previously classified as a VUS-possibly pathogenic variant that was converted during ClinVar submission to likely pathogenic in 2011. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely benign, and one laboratory classified the variant as uncertain significance. No new evidence supporting a pathogenic outcome has emerged over a span of eight years (2011-2019). Based on the evidence outlined above, the variant was classified as likely benign. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | May 08, 2017 | - - |
Nephrolithiasis/nephrocalcinosis Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 02, 2023 | 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. - |
Familial hypocalciuric hypercalcemia 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Autosomal dominant hypocalcemia 1;C1809471:Familial hypocalciuric hypercalcemia Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 18, 2023 | - - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 30, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at