chr3-122257241-G-A

Position:

• chr3-122257241-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_000388.4(CASR):​c.346G>A​(p.Ala116Thr) 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. 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. A116G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CASR NM_000388.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.14

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 3 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-122257241-G-C is described in Lovd as [Pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CASR. . Gene score misZ 3.1237 (greater than the threshold 3.09). Trascript score misZ 4.8257 (greater than threshold 3.09). GenCC has associacion of gene with 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, 0.847
• PP5: Variant 3-122257241-G-A is Pathogenic according to our data. Variant chr3-122257241-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8321.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-122257241-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASR	NM_000388.4	c.346G>A	p.Ala116Thr	missense_variant	3/7	ENST00000639785.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASR	ENST00000639785.2	c.346G>A	p.Ala116Thr	missense_variant	3/7	1	NM_000388.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant hypocalcemia 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 1996

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 08, 2018

DNA sequence analysis of the CASR gene demonstrated a sequence change, c.346G>A, in exon 3 that results in an amino acid change, p.Ala116Thr. The p.Ala116Thr change affects a highly conserved amino acid residue located in a domain of the CASR protein that is known to be functional. The p.Ala116Thr substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This particular sequence change has been previously described as a de novo variant in one family with autosomal dominant hypocalcemia (PMID: 8733126). Affected members had low serum parathyroid hormone (PTH) and low serum calcium concentrations and presented with muscle cramps. Despite low serum calcium concentrations, affected members had significant hypercalciuria that was suggestive of the p.Ala116Thr being an activating mutation (PMID: 8733126). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T;T;.;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	.;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.85	D;D;D;D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	0.63	N;N;N;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	0.27	.;.;N;N
REVEL	Pathogenic	0.67
Sift	Benign	0.62	.;.;T;T
Sift4G	Benign	0.49	.;.;T;T
Polyphen		0.99	D;D;.;.
Vest4		0.89, 0.88
MutPred		0.74		Gain of ubiquitination at K119 (P = 0.0654);Gain of ubiquitination at K119 (P = 0.0654);Gain of ubiquitination at K119 (P = 0.0654);Gain of ubiquitination at K119 (P = 0.0654);
MVP		0.98
MPC		1.6
ClinPred		0.83	D
GERP RS		5.8
Varity_R		0.67
gMVP		0.57

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: rs104893691; hg19: chr3-121976088;