rs1801725

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2_SupportingPP2BP4_Moderate

The NM_000388(CASR):c.2956G>A(p.Ala986Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD Genomes project. In-silico tool predicts a benign outcome for this variant. 13/20 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. A986S) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Consequence

CASR
NM_000388 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.23

Links

CASR (HGNC:1514):

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a region_of_interest Disordered (size 20) in uniprot entity CASR_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_000388

PM2

Very rare variant; Number of alleles below threshold, Median coverage is 33.

PP2

Missense variant where missense usually causes diseases, CASR

BP4

Computational evidence support a benign effect (MetaRNN=0.15316647).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASR	NM_000388.4 linkuse as main transcript	c.2956G>A	p.Ala986Thr	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.2956G>A	p.Ala986Thr	missense_variant	7/7	1	NM_000388.4	P1	P41180-1
CASR	ENST00000498619.4 linkuse as main transcript	c.2986G>A	p.Ala996Thr	missense_variant	7/7	1			P41180-2
CASR	ENST00000638421.1 linkuse as main transcript	c.2956G>A	p.Ala986Thr	missense_variant	7/7	5		P1	P41180-1
CASR	ENST00000490131.7 linkuse as main transcript	c.2725G>A	p.Ala909Thr	missense_variant	5/5	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461864

Hom.:

AF XY:

0.00000413

AC XY:

AN XY:

727226

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Autosomal dominant hypocalcemia 1;C1809471:Familial hypocalciuric hypercalcemia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 31, 2021

This sequence change replaces alanine with threonine at codon 986 of the CASR protein (p.Ala986Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with CASR-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

0.00098

BayesDel_noAF

Benign

-0.24

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.33

T;T;.;.

Eigen

Benign

-0.12

Eigen_PC

Benign

0.0068

FATHMM_MKL

Uncertain

0.96

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.15

T;T;T;T

MetaSVM

Uncertain

-0.023

MutationAssessor

Benign

1.8

L;L;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.35

Polyphen

0.35

B;B;.;.

Vest4

0.096

MutPred

0.14

.;.;Gain of loop (P = 0.0435);.;

MVP

0.93

MPC

0.58

ClinPred

0.58

GERP RS

4.9

Varity_R

0.15

gMVP

0.33

Splicing

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

Links

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over