3-122257358-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP2PP3_Moderate

The NM_000388.4(CASR):​c.463A>T​(p.Asn155Tyr) variant causes a missense 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Consequence

CASR
NM_000388.4 missense

Scores

8
9
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.21
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1
In a helix (size 12) in uniprot entity CASR_HUMAN there are 8 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
MetaRNN computational evidence supports a deleterious effect, 0.884

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CASRNM_000388.4 linkc.463A>T p.Asn155Tyr missense_variant 3/7 ENST00000639785.2 NP_000379.3 P41180-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CASRENST00000639785.2 linkc.463A>T p.Asn155Tyr missense_variant 3/71 NM_000388.4 ENSP00000491584.2 P41180-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.56
BayesDel_addAF
Pathogenic
0.28
D
BayesDel_noAF
Pathogenic
0.16
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.72
D;D;.;.
Eigen
Pathogenic
0.83
Eigen_PC
Pathogenic
0.79
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.92
.;D;D;D
M_CAP
Uncertain
0.26
D
MetaRNN
Pathogenic
0.88
D;D;D;D
MetaSVM
Uncertain
0.60
D
MutationAssessor
Pathogenic
2.9
M;M;M;.
PrimateAI
Uncertain
0.73
T
PROVEAN
Uncertain
-3.6
.;.;D;D
REVEL
Pathogenic
0.83
Sift
Uncertain
0.021
.;.;D;D
Sift4G
Benign
0.064
.;.;T;T
Polyphen
1.0
D;D;.;.
Vest4
0.84, 0.86
MutPred
0.68
Loss of glycosylation at S150 (P = 0.0323);Loss of glycosylation at S150 (P = 0.0323);Loss of glycosylation at S150 (P = 0.0323);Loss of glycosylation at S150 (P = 0.0323);
MVP
0.99
MPC
1.7
ClinPred
0.99
D
GERP RS
5.8
Varity_R
0.73
gMVP
0.94

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1553766282; hg19: chr3-121976205; API