3-122262332-G-C

Position:

chr3-122262332-G-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBS1_SupportingBS2

The NM_000388.4(CASR):c.1297G>C(p.Asp433His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000737 in 1,614,100 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000080 ( 2 hom. )

Consequence

CASR
NM_000388.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 8.15

Variant links:

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]

CASR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

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=0.244742).

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00008 (117/1461778) while in subpopulation SAS AF= 0.00132 (114/86254). AF 95% confidence interval is 0.00112. There are 2 homozygotes in gnomad4_exome. There are 88 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASR	NM_000388.4 linkuse as main transcript	c.1297G>C	p.Asp433His	missense_variant	4/7	ENST00000639785.2	NP_000379.3	P41180-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CASR	ENST00000639785.2 linkuse as main transcript	c.1297G>C	p.Asp433His	missense_variant	4/7	1	NM_000388.4	ENSP00000491584.2	P41180-1
CASR	ENST00000498619.4 linkuse as main transcript	c.1297G>C	p.Asp433His	missense_variant	4/7	1		ENSP00000420194.1	P41180-2
CASR	ENST00000638421.1 linkuse as main transcript	c.1297G>C	p.Asp433His	missense_variant	4/7	5		ENSP00000492190.1	P41180-1
CASR	ENST00000490131.7 linkuse as main transcript	c.1297G>C	p.Asp433His	missense_variant	3/5	5		ENSP00000418685.2	A0A1X7SBX3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000207

AC:

AN:

251136

Hom.:

AF XY:

0.000236

AC XY:

AN XY:

135714

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00160

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.0000800

AC:

117

AN:

1461778

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00132

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152322

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.000198

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial hypocalciuric hypercalcemia 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

Feb 14, 2023

The missense variant c.1297G>C (p.Asp433His) in the CASR gene has been reported previously in heterozygous state in individuals affected with Tropical Calcific Pancreatitis (TCP). Molecular dynamics simulation, along with essential dynamics analysis indicates that the mutation D433H has a significant impact on protein structure (Shrivastava et al., 2022; Murugaian et al., 2008). This variant is reported with the allele frequency (0.02%) in the gnomAD and novel in 1000 genome database. It is submitted to ClinVar as Uncertain significance. The amino acid Aspartic Acid at position 433 is changed to a Histidine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted as damaging by SIFT. The amino acid change p.Asp433His in CASR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Although this variant has a higher MAF, based on molecular dynamics and clinvar reports, this variant is classified as Variant of uncertain significance. Classification is likely to change as more literature becomes available. -

Autosomal dominant hypocalcemia 1;C1809471:Familial hypocalciuric hypercalcemia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 28, 2023

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 433 of the CASR protein (p.Asp433His). This variant is present in population databases (rs199511990, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with tropical chronic pancreatitis (PMID: 18938753). ClinVar contains an entry for this variant (Variation ID: 463897). 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 disruptive. 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. -

Autosomal dominant hypocalcemia 1;C0342637:Familial hypocalciuric hypercalcemia 1;C1832615:Neonatal severe primary hyperparathyroidism;C2752062:Epilepsy, idiopathic generalized, susceptibility to, 8

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 31, 2021

- -

Nephrolithiasis/nephrocalcinosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 02, 2023

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

CASR-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 07, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Uncertain

0.088

BayesDel_noAF

Pathogenic

0.33

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.73

D;D;.;.

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.73

.;T;T;T

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.24

T;T;T;T

MetaSVM

Uncertain

0.27

MutationAssessor

Uncertain

2.1

M;M;M;.

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-3.3

.;.;D;D

REVEL

Pathogenic

0.74

Sift

Benign

0.049

.;.;D;T

Sift4G

Uncertain

0.0080

.;.;D;D

Polyphen

0.97

D;D;.;.

Vest4

0.94, 0.93

MutPred

0.52

Loss of glycosylation at T436 (P = 0.0599);Loss of glycosylation at T436 (P = 0.0599);Loss of glycosylation at T436 (P = 0.0599);Loss of glycosylation at T436 (P = 0.0599);

MVP

0.97

MPC

1.7

ClinPred

0.17

GERP RS

4.0

Varity_R

0.73

gMVP

0.77

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over