rs1553769127

chr3-122284473-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PP2 PP3_Strong

The NM_000388.4(CASR):c.2519C>T(p.Ala840Val) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CASR NM_000388.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.89

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_000388.4
• PP2: Missense variant where missense usually causes diseases, CASR
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASR	NM_000388.4	c.2519C>T	p.Ala840Val	missense_variant	7/7	ENST00000639785.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASR	ENST00000639785.2	c.2519C>T	p.Ala840Val	missense_variant	7/7	1	NM_000388.4	P1
CASR	ENST00000498619.4	c.2549C>T	p.Ala850Val	missense_variant	7/7	1
CASR	ENST00000638421.1	c.2519C>T	p.Ala840Val	missense_variant	7/7	5		P1
CASR	ENST00000490131.7	c.2288C>T	p.Ala763Val	missense_variant	5/5	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461126 Hom.: 0 Cov.: 71 AF XY: 0.00 AC XY: 0 AN XY: 726932

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Nov 29, 2016

- -

Autosomal dominant hypocalcemia 1;C1809471:Familial hypocalciuric hypercalcemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 18, 2022

Experimental studies have shown that this missense change affects CASR function (PMID: 31063613). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 840 of the CASR protein (p.Ala840Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypocalcemia and/or hypoparathyroidism (PMID: 19549694, 24948345, 31063613; Invitae). ClinVar contains an entry for this variant (Variation ID: 446993). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.77	D;D;.;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Benign	2.0	M;M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.83	D
Polyphen		1.0	D;D;.;.
Vest4		0.98
MutPred		0.87		.;.;Loss of sheet (P = 0.1158);.;
MVP		1.0
MPC		1.5
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.89
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs1553769127; hg19: chr3-122003320;