chr3-122284359-A-G

Position:

chr3-122284359-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM5PP2PP3PP5_Very_Strong

The NM_000388.4(CASR):c.2405A>G(p.Asn802Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000805 in 1,614,010 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. N802D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

CASR
NM_000388.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 5.75

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 Pathogenic. Variant got 14 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000388.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-122284358-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1338619.Status of the report is criteria_provided_single_submitter, 1 stars.

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, 0.796

PP5

Variant 3-122284359-A-G is Pathogenic according to our data. Variant chr3-122284359-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 379931.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASR	NM_000388.4 linkuse as main transcript	c.2405A>G	p.Asn802Ser	missense_variant	7/7	ENST00000639785.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASR	ENST00000639785.2 linkuse as main transcript	c.2405A>G	p.Asn802Ser	missense_variant	7/7	1	NM_000388.4	P1	P41180-1
CASR	ENST00000498619.4 linkuse as main transcript	c.2435A>G	p.Asn812Ser	missense_variant	7/7	1			P41180-2
CASR	ENST00000638421.1 linkuse as main transcript	c.2405A>G	p.Asn802Ser	missense_variant	7/7	5		P1	P41180-1
CASR	ENST00000490131.7 linkuse as main transcript	c.2174A>G	p.Asn725Ser	missense_variant	5/5	5

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251378

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

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:

0.00000752

AC:

AN:

1461800

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000324

Hom.:

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 15, 2015	The N802S missense variant in the CASR gene has been reported previously in association with familialhypercalciuric hypocalcemia in a female patient with milder phenotype (Lia-Baldini et al., 2013). N802Swas not observed at any significant frequency in approximately 6,500 individuals of European and AfricanAmerican ancestry by the NHLBI Exome Sequencing Project. It is a conservative amino acid substitution,which is not likely to impact secondary protein structure as these residues share similar properties. Thissubstitution occurs at a position where amino acids with similar properties to asparagine are toleratedacross species. In silico analysis predicts this variant is probably damaging to the protein structure/function.In addition, missense variants at the same codon (N802I) and in nearby residues (R795W, P798T/L,E799K, N800T, A804D, F806S/L, M811V) have been reported in the Human Gene Mutation Database inassociation with CASR-related disorders (Stenson et al., 2014), supporting the functional importance of thisregion of the protein. Therefore, we consider N802S to be a pathogenic variant. -

CASR-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Jan 23, 2024

PS3, PM1, PM2, PM5_Supporting, PP2 -

Autosomal dominant hypocalcemia 1;C1809471:Familial hypocalciuric hypercalcemia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 15, 2023

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 802 of the CASR protein (p.Asn802Ser). This variant is present in population databases (rs140022350, gnomAD 0.01%). This missense change has been observed in individual(s) with familial hypocalciuric hypercalcemia (PMID: 23169696, 26963950, 32386559). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 379931). 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. Experimental studies have shown that this missense change affects CASR function (PMID: 23169696, 32386559). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 09, 2021

- -

Familial hypocalciuric hypercalcemia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 26, 2024

Variant summary: CASR c.2405A>G (p.Asn802Ser) results in a conservative amino acid change located in the GPCR family 3, C-terminal domain (IPR017978) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 1614010 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CASR causing Familial Hypocalciuric Hypercalcemia (8.1e-06 vs 1.3e-05), allowing no conclusion about variant significance. c.2405A>G has been reported in the literature in individuals affected with Familial Hypocalciuric Hypercalcemia (e.g. Lia-Baldini_2013, Vargas-Poussou_2016, Dershem_2020). These data indicate that the variant is likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function (e.g. Lia-Baldini_2013, Dershem_2020). The variant was found to have reduced plasma membrane localization and a response to extracellular calcium that was approximately 50% of the WT protein. The following publications have been ascertained in the context of this evaluation (PMID: 26963950, 32386559, 23169696). ClinVar contains an entry for this variant (Variation ID: 379931). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.055

BayesDel_noAF

Uncertain

-0.080

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.86

D;D;.;.

Eigen

Uncertain

0.66

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.96

.;D;D;D

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.80

D;D;D;D

MetaSVM

Pathogenic

0.85

MutationAssessor

Uncertain

2.2

M;M;.;.

MutationTaster

Benign

0.98

D;D;D

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-3.9

.;.;D;.

REVEL

Pathogenic

0.67

Sift

Benign

0.054

.;.;T;.

Sift4G

Uncertain

0.0070

.;.;D;.

Polyphen

0.83

P;P;.;.

Vest4

0.85

MVP

0.92

MPC

1.3

ClinPred

0.93

GERP RS

6.0

Varity_R

0.38

gMVP

0.68

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