3-122284671-C-A

Position:

• chr3-122284671-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

The NM_000388.4(CASR):​c.2717C>A​(p.Thr906Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T906M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CASR NM_000388.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.42

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a compositionally_biased_region Polar residues (size 69) in uniprot entity CASR_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in NM_000388.4
• PM2: Very rare variant in population databases, with high coverage
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.31307667).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASR	NM_000388.4	c.2717C>A	p.Thr906Lys	missense_variant	7/7	ENST00000639785.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASR	ENST00000639785.2	c.2717C>A	p.Thr906Lys	missense_variant	7/7	1	NM_000388.4	P1
CASR	ENST00000498619.4	c.2747C>A	p.Thr916Lys	missense_variant	7/7	1
CASR	ENST00000638421.1	c.2717C>A	p.Thr906Lys	missense_variant	7/7	5		P1
CASR	ENST00000490131.7	c.2486C>A	p.Thr829Lys	missense_variant	5/5	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 70

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 17, 2023

This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 906 of the CASR protein (p.Thr906Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CASR-related conditions. ClinVar contains an entry for this variant (Variation ID: 840869). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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	Benign	0.18
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.40	T;T;.;.
Eigen	Benign	-0.13
Eigen_PC	Benign	0.030
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.85	.;D;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.31	T;T;T;T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	1.6	L;L;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.2	.;.;N;.
REVEL	Uncertain	0.46
Sift	Uncertain	0.0030	.;.;D;.
Sift4G	Uncertain	0.0060	.;.;D;.
Polyphen		0.14	B;B;.;.
Vest4		0.37
MutPred		0.26		.;.;Gain of glycosylation at S921 (P = 0.0077);.;
MVP		0.88
MPC		0.84
ClinPred		0.89	D
GERP RS		5.0
Varity_R		0.18
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200357435; hg19: chr3-122003518;