chr3-122284967-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM1PP2BP4_Moderate
The NM_000388.4(CASR):c.3013G>A(p.Asp1005Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000121 in 1,614,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000388.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CASR | ENST00000639785.2 | c.3013G>A | p.Asp1005Asn | missense_variant | 7/7 | 1 | NM_000388.4 | ENSP00000491584.2 | ||
CASR | ENST00000498619.4 | c.3043G>A | p.Asp1015Asn | missense_variant | 7/7 | 1 | ENSP00000420194.1 | |||
CASR | ENST00000638421.1 | c.3013G>A | p.Asp1005Asn | missense_variant | 7/7 | 5 | ENSP00000492190.1 | |||
CASR | ENST00000490131.7 | c.2782G>A | p.Asp928Asn | missense_variant | 5/5 | 5 | ENSP00000418685.2 |
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152188Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000597 AC: 15AN: 251326Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135860
GnomAD4 exome AF: 0.000127 AC: 185AN: 1461872Hom.: 0 Cov.: 71 AF XY: 0.000138 AC XY: 100AN XY: 727242
GnomAD4 genome AF: 0.0000723 AC: 11AN: 152188Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6AN XY: 74338
ClinVar
Submissions by phenotype
Autosomal dominant hypocalcemia 1;C0342637:Familial hypocalciuric hypercalcemia 1;C1832615:Neonatal severe primary hyperparathyroidism;C2752062:Epilepsy, idiopathic generalized, susceptibility to, 8 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jun 13, 2024 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 15, 2017 | The D1005N variant in the CASR gene has been previously reported in an individual with familial hypocalciuric hypercalcemia; however, functional studies did not demonstrate a significant reduction in receptor calcium response (Rus et al., 2008). This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The D1005N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position where amino acids with similar properties to Aspartic Acid are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret D1005N as a variant of uncertain significance. - |
Nephrolithiasis/nephrocalcinosis Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 15, 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. - |
Autosomal dominant hypocalcemia 1;C1809471:Familial hypocalciuric hypercalcemia Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 29, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at