3-122284539-T-C

Position:

chr3-122284539-T-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1PP2PP3BP6BS1

The NM_000388.4(CASR):c.2585T>C(p.Phe862Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000415 in 1,613,808 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 Conflicting classifications of pathogenicity (no stars).

Frequency

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

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

CASR
NM_000388.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 8.00

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 -1 ACMG points.

PM1

In a transmembrane_region Helical; Name=7 (size 25) in uniprot entity CASR_HUMAN there are 12 pathogenic changes around while only 2 benign (86%) in NM_000388.4

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, 0.775

BP6

Variant 3-122284539-T-C is Benign according to our data. Variant chr3-122284539-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 532619.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000445 (65/1461580) while in subpopulation SAS AF= 0.000672 (58/86258). AF 95% confidence interval is 0.000533. There are 0 homozygotes in gnomad4_exome. There are 48 alleles in male gnomad4_exome subpopulation. Median coverage is 70. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASR	NM_000388.4 linkuse as main transcript	c.2585T>C	p.Phe862Ser	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.2585T>C	p.Phe862Ser	missense_variant	7/7	1	NM_000388.4	P1	P41180-1
CASR	ENST00000498619.4 linkuse as main transcript	c.2615T>C	p.Phe872Ser	missense_variant	7/7	1			P41180-2
CASR	ENST00000638421.1 linkuse as main transcript	c.2585T>C	p.Phe862Ser	missense_variant	7/7	5		P1	P41180-1
CASR	ENST00000490131.7 linkuse as main transcript	c.2354T>C	p.Phe785Ser	missense_variant	5/5	5

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152228

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:

0.000119

AC:

AN:

251142

Hom.:

AF XY:

0.000184

AC XY:

AN XY:

135804

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:

0.000882

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000445

AC:

AN:

1461580

Hom.:

Cov.:

AF XY:

0.0000660

AC XY:

AN XY:

727138

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:

0.000672

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74364

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

Alfa

AF:

0.0000425

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.000115

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal dominant hypocalcemia 1;C1809471:Familial hypocalciuric hypercalcemia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 06, 2023

This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 862 of the CASR protein (p.Phe862Ser). This variant is present in population databases (rs201328344, gnomAD 0.09%). 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: 532619). 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. -

Nephrolithiasis/nephrocalcinosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 24, 2024

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Uncertain

0.074

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

D;D;.;.

Eigen

Uncertain

0.61

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.87

.;D;D;D

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.77

D;D;D;D

MetaSVM

Uncertain

0.58

MutationAssessor

Benign

1.8

L;L;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-3.4

.;.;D;.

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0020

.;.;D;.

Sift4G

Uncertain

0.0030

.;.;D;.

Polyphen

0.99

D;D;.;.

Vest4

0.76

MutPred

0.82

.;.;Gain of disorder (P = 0.0137);.;

MVP

0.95

MPC

1.3

ClinPred

0.20

GERP RS

5.8

Varity_R

0.69

gMVP

0.88

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