rs746005172

Positions:

• chr3-122284745-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 5P and 2B. PM1 PM2 PP2 BP4_Moderate

The NM_000388.4(CASR):​c.2791A>C​(p.Lys931Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. K931R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CASR NM_000388.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.47

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 3 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 where missense usually causes diseases, CASR
• BP4: Computational evidence support a benign effect (MetaRNN=0.1237292).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASR	NM_000388.4	c.2791A>C	p.Lys931Gln	missense_variant	7/7	ENST00000639785.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASR	ENST00000639785.2	c.2791A>C	p.Lys931Gln	missense_variant	7/7	1	NM_000388.4	P1
CASR	ENST00000498619.4	c.2821A>C	p.Lys941Gln	missense_variant	7/7	1
CASR	ENST00000638421.1	c.2791A>C	p.Lys931Gln	missense_variant	7/7	5		P1
CASR	ENST00000490131.7	c.2560A>C	p.Lys854Gln	missense_variant	5/5	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 250844 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135648

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461838 Hom.: 0 Cov.: 70 AF XY: 0.00000138 AC XY: 1 AN XY: 727212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

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

Jul 10, 2022

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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 532580). This variant has not been reported in the literature in individuals affected with CASR-related conditions. This variant is present in population databases (rs746005172, gnomAD 0.006%). This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 931 of the CASR protein (p.Lys931Gln). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T;T;.;.
Eigen	Benign	-0.22
Eigen_PC	Benign	0.011
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Uncertain	0.088	D
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	1.1	L;L;.;.
MutationTaster	Benign	0.51	N;N;N
PrimateAI	Benign	0.45	T
Polyphen		0.0010	B;B;.;.
Vest4		0.21
MutPred		0.26		.;.;Loss of ubiquitination at K941 (P = 0.0074);.;
MVP		0.82
MPC		0.64
ClinPred		0.14	T
GERP RS		4.7
Varity_R		0.15
gMVP		0.25

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: rs746005172; hg19: chr3-122003592;