rs104893706

chr3-122284482-C-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_000388.4(CASR):c.2528C>A(p.Ala843Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A843T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CASR NM_000388.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 6.16

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_000388.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CASR
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978
• PP5: Variant 3-122284482-C-A is Pathogenic according to our data. Variant chr3-122284482-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8343.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-122284482-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASR	NM_000388.4	c.2528C>A	p.Ala843Glu	missense_variant	7/7	ENST00000639785.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASR	ENST00000639785.2	c.2528C>A	p.Ala843Glu	missense_variant	7/7	1	NM_000388.4	P1
CASR	ENST00000498619.4	c.2558C>A	p.Ala853Glu	missense_variant	7/7	1
CASR	ENST00000638421.1	c.2528C>A	p.Ala843Glu	missense_variant	7/7	5		P1
CASR	ENST00000490131.7	c.2297C>A	p.Ala766Glu	missense_variant	5/5	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 70

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant hypocalcemia 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The CASR c.2528C>A (p.Ala843Glu) variant has been reported in heterozygous state in individuals affected with Hyperparathyroidism, Neonatal Severe (Egbuna and Brown, 2008). This variant has been submitted to ClinVar as Pathogenic. The p.Ala843Glu variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The amino acid Ala at position 843 is changed to a Glu changing protein sequence and it might alter its composition and physicochemical properties. The amino acid change p.Ala843Glu in CASR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 31, 2002	- -

Bartter syndrome with hypocalcemia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 31, 2002

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
Cadd	Pathogenic	31
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D;D;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.2	M;M;.;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.85	D
Polyphen		1.0	D;D;.;.
Vest4		0.97
MutPred		0.89		.;.;Loss of sheet (P = 0.1158);.;
MVP		1.0
MPC		1.7
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.96
gMVP		0.96

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: rs104893706; hg19: chr3-122003329;