rs1042636

Variant names:

• chr3-122284922-A-G
• rs1042636
• NM_000388.4:c.2968A>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000388.4(CASR):​c.2968A>G​(p.Arg990Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 1,614,046 control chromosomes in the GnomAD database, including 15,462 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R990K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.098 (1495 hom., cov: 33)
  • Exomes 𝑓: 0.10 (13967 hom.)
• Consequence: CASR NM_000388.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 2.67
• Publications: 187 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant hypocalcemia 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Illumina, Labcorp Genetics (formerly Invitae), ClinGen
• familial hypocalciuric hypercalcemia 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Illumina, Orphanet, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• neonatal severe primary hyperparathyroidism

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)
• autosomal dominant hypocalcemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• epilepsy, idiopathic generalized, susceptibility to, 8

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• epilepsy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• PP2: Missense variant in the CASR gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 114 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 3.1237 (above the threshold of 3.09). Trascript score misZ: 4.8257 (above the threshold of 3.09). GenCC associations: The gene is linked to autosomal dominant hypocalcemia, familial hypocalciuric hypercalcemia 1, neonatal severe primary hyperparathyroidism, autosomal dominant hypocalcemia 1, epilepsy, epilepsy, idiopathic generalized, susceptibility to, 8.
• BP4: Computational evidence support a benign effect (MetaRNN=3.8957596E-4).
• BP6: Variant 3-122284922-A-G is Benign according to our data. Variant chr3-122284922-A-G is described in ClinVar as Benign. ClinVar VariationId is 198071.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.504 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000388.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASR	NM_000388.4	MANE Select	c.2968A>G	p.Arg990Gly	missense	Exon 7 of 7	NP_000379.3
	CASR	NM_001178065.2		c.2998A>G	p.Arg1000Gly	missense	Exon 7 of 7	NP_001171536.2	P41180-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASR	ENST00000639785.2	TSL:1 MANE Select	c.2968A>G	p.Arg990Gly	missense	Exon 7 of 7	ENSP00000491584.2	P41180-1
	CASR	ENST00000498619.4	TSL:1	c.2998A>G	p.Arg1000Gly	missense	Exon 7 of 7	ENSP00000420194.1	P41180-2
	CASR	ENST00000638421.1	TSL:5	c.2968A>G	p.Arg990Gly	missense	Exon 7 of 7	ENSP00000492190.1	P41180-1

Frequencies

GnomAD3 genomes AF: 0.0975 AC: 14837 AN: 152102 Hom.: 1486 Cov.: 33

Gnomad AFR AF: 0.0412

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.0450

Gnomad EAS AF: 0.519

Gnomad SAS AF: 0.230

Gnomad FIN AF: 0.100

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0766

Gnomad OTH AF: 0.0884

GnomAD2 exomes AF: 0.151 AC: 37928 AN: 251272 AF XY: 0.146

Gnomad AFR exome AF: 0.0419

Gnomad AMR exome AF: 0.270

Gnomad ASJ exome AF: 0.0401

Gnomad EAS exome AF: 0.530

Gnomad FIN exome AF: 0.106

Gnomad NFE exome AF: 0.0743

Gnomad OTH exome AF: 0.115

GnomAD4 exome AF: 0.103 AC: 150360 AN: 1461826 Hom.: 13967 Cov.: 73 AF XY: 0.105 AC XY: 76083 AN XY: 727222

African (AFR) AF: 0.0388 AC: 1298 AN: 33480

American (AMR) AF: 0.257 AC: 11481 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.0406 AC: 1062 AN: 26136

East Asian (EAS) AF: 0.541 AC: 21474 AN: 39694

South Asian (SAS) AF: 0.202 AC: 17410 AN: 86256

European-Finnish (FIN) AF: 0.106 AC: 5640 AN: 53418

Middle Eastern (MID) AF: 0.0388 AC: 224 AN: 5768

European-Non Finnish (NFE) AF: 0.0761 AC: 84638 AN: 1111984

Other (OTH) AF: 0.118 AC: 7133 AN: 60396

GnomAD4 genome AF: 0.0977 AC: 14870 AN: 152220 Hom.: 1495 Cov.: 33 AF XY: 0.103 AC XY: 7699 AN XY: 74432

African (AFR) AF: 0.0412 AC: 1713 AN: 41550

American (AMR) AF: 0.177 AC: 2706 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0450 AC: 156 AN: 3468

East Asian (EAS) AF: 0.520 AC: 2692 AN: 5176

South Asian (SAS) AF: 0.231 AC: 1116 AN: 4822

European-Finnish (FIN) AF: 0.100 AC: 1063 AN: 10592

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0766 AC: 5208 AN: 68006

Other (OTH) AF: 0.0932 AC: 197 AN: 2114

Alfa AF: 0.0881 Hom.: 4894

Bravo AF: 0.100

TwinsUK AF: 0.0734 AC: 272

ALSPAC AF: 0.0802 AC: 309

ESP6500AA AF: 0.0429 AC: 189

ESP6500EA AF: 0.0731 AC: 629

ExAC AF: 0.145 AC: 17658

Asia WGS AF: 0.367 AC: 1274 AN: 3478

EpiCase AF: 0.0721

EpiControl AF: 0.0666

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Familial hypocalciuric hypercalcemia 1 (2)
-	-	2	not provided (2)
-	-	1	Autosomal dominant hypocalcemia 1 (1)
-	-	1	Familial hypocalciuric hypercalcemia;C3715128:Autosomal dominant hypocalcemia 1 (1)
-	-	1	Familial hypoparathyroidism (1)
-	-	1	Neonatal severe primary hyperparathyroidism (1)
-	-	1	Nephrolithiasis/nephrocalcinosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.068
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.00039	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.7
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.79	N
REVEL	Uncertain	0.44
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.15	B
Vest4		0.051
MPC		0.77
ClinPred		0.027	T
GERP RS		3.3
Varity_R		0.29
gMVP		0.44
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1042636; hg19: chr3-122003769; COSMIC: COSV56139527;