rs1553766913

chr3-122262339-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_000388.4(CASR):c.1304A>T(p.Tyr435Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. Y435C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CASR NM_000388.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.74

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CASR
• BP4: Computational evidence support a benign effect (MetaRNN=0.18083712).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASR	NM_000388.4	c.1304A>T	p.Tyr435Phe	missense_variant	4/7	ENST00000639785.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASR	ENST00000639785.2	c.1304A>T	p.Tyr435Phe	missense_variant	4/7	1	NM_000388.4	P1
CASR	ENST00000498619.4	c.1304A>T	p.Tyr435Phe	missense_variant	4/7	1
CASR	ENST00000638421.1	c.1304A>T	p.Tyr435Phe	missense_variant	4/7	5		P1
CASR	ENST00000490131.7	c.1304A>T	p.Tyr435Phe	missense_variant	3/5	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

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 08, 2017

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with CASR-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces tyrosine with phenylalanine at codon 435 of the CASR protein (p.Tyr435Phe). The tyrosine residue is highly conserved and there is a small physicochemical difference between tyrosine and phenylalanine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	21
Dann	Benign	0.75
DEOGEN2	Benign	0.34	T;T;.;.
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.82	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.18	T;T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.2	L;L;L;.
MutationTaster	Benign	0.56	N;N;N
PrimateAI	Uncertain	0.73	T
Polyphen		0.0010	B;B;.;.
Vest4		0.25, 0.25
MutPred		0.53		Loss of catalytic residue at I434 (P = 0.0381);Loss of catalytic residue at I434 (P = 0.0381);Loss of catalytic residue at I434 (P = 0.0381);Loss of catalytic residue at I434 (P = 0.0381);
MVP		0.81
MPC		0.56
ClinPred		0.75	D
GERP RS		1.9
Varity_R		0.25
gMVP		0.38

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: rs1553766913; hg19: chr3-121981186; COSMIC: COSV56135545; COSMIC: COSV56135545;