rs1801726

Variant names:

• chr3-122284985-G-C
• rs1801726
• NM_000388.4:c.3031G>C

Your query was ambiguous. Multiple possible variants found:

• chr3-122284985-G-C
• chr3-122284985-G-A

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.3031G>C​(p.Glu1011Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.953 in 1,614,136 control chromosomes in the GnomAD database, including 733,487 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. E1011E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.92 (64966 hom., cov: 32)
  • Exomes 𝑓: 0.96 (668521 hom.)
• Consequence: CASR NM_000388.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.20
• Publications: 107 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 neonatal severe primary hyperparathyroidism, autosomal dominant hypocalcemia 1, familial hypocalciuric hypercalcemia 1, epilepsy, autosomal dominant hypocalcemia, epilepsy, idiopathic generalized, susceptibility to, 8.
• BP4: Computational evidence support a benign effect (MetaRNN=7.8220154E-7).
• BP6: Variant 3-122284985-G-C is Benign according to our data. Variant chr3-122284985-G-C is described in ClinVar as Benign. ClinVar VariationId is 166799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.959 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.3031G>C	p.Glu1011Gln	missense	Exon 7 of 7	NP_000379.3
	CASR	NM_001178065.2		c.3061G>C	p.Glu1021Gln	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.3031G>C	p.Glu1011Gln	missense	Exon 7 of 7	ENSP00000491584.2	P41180-1
	CASR	ENST00000498619.4	TSL:1	c.3061G>C	p.Glu1021Gln	missense	Exon 7 of 7	ENSP00000420194.1	P41180-2
	CASR	ENST00000638421.1	TSL:5	c.3031G>C	p.Glu1011Gln	missense	Exon 7 of 7	ENSP00000492190.1	P41180-1

Frequencies

GnomAD3 genomes AF: 0.922 AC: 140224 AN: 152142 Hom.: 64924 Cov.: 32

Gnomad AFR AF: 0.826

Gnomad AMI AF: 0.946

Gnomad AMR AF: 0.969

Gnomad ASJ AF: 0.984

Gnomad EAS AF: 0.981

Gnomad SAS AF: 0.956

Gnomad FIN AF: 0.917

Gnomad MID AF: 0.972

Gnomad NFE AF: 0.959

Gnomad OTH AF: 0.939

GnomAD2 exomes AF: 0.950 AC: 238820 AN: 251384 AF XY: 0.952

Gnomad AFR exome AF: 0.824

Gnomad AMR exome AF: 0.982

Gnomad ASJ exome AF: 0.985

Gnomad EAS exome AF: 0.984

Gnomad FIN exome AF: 0.918

Gnomad NFE exome AF: 0.955

Gnomad OTH exome AF: 0.963

GnomAD4 exome AF: 0.956 AC: 1397542 AN: 1461876 Hom.: 668521 Cov.: 65 AF XY: 0.956 AC XY: 695263 AN XY: 727242

African (AFR) AF: 0.820 AC: 27446 AN: 33478

American (AMR) AF: 0.981 AC: 43858 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.984 AC: 25716 AN: 26136

East Asian (EAS) AF: 0.985 AC: 39092 AN: 39698

South Asian (SAS) AF: 0.952 AC: 82113 AN: 86256

European-Finnish (FIN) AF: 0.919 AC: 49074 AN: 53420

Middle Eastern (MID) AF: 0.972 AC: 5607 AN: 5768

European-Non Finnish (NFE) AF: 0.959 AC: 1066853 AN: 1112002

Other (OTH) AF: 0.957 AC: 57783 AN: 60394

GnomAD4 genome AF: 0.922 AC: 140324 AN: 152260 Hom.: 64966 Cov.: 32 AF XY: 0.923 AC XY: 68682 AN XY: 74436

African (AFR) AF: 0.826 AC: 34290 AN: 41522

American (AMR) AF: 0.969 AC: 14831 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.984 AC: 3415 AN: 3472

East Asian (EAS) AF: 0.981 AC: 5090 AN: 5188

South Asian (SAS) AF: 0.956 AC: 4616 AN: 4826

European-Finnish (FIN) AF: 0.917 AC: 9716 AN: 10592

Middle Eastern (MID) AF: 0.969 AC: 285 AN: 294

European-Non Finnish (NFE) AF: 0.959 AC: 65229 AN: 68036

Other (OTH) AF: 0.940 AC: 1989 AN: 2116

Alfa AF: 0.957 Hom.: 52739

Bravo AF: 0.923

TwinsUK AF: 0.962 AC: 3568

ALSPAC AF: 0.959 AC: 3696

ESP6500AA AF: 0.836 AC: 3685

ESP6500EA AF: 0.960 AC: 8252

ExAC AF: 0.945 AC: 114677

Asia WGS AF: 0.955 AC: 3320 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Autosomal dominant hypocalcemia 1 (1)
-	-	1	Autosomal dominant hypocalcemia 1;C1809471:Familial hypocalciuric hypercalcemia (1)
-	-	1	Familial hypocalciuric hypercalcemia 1 (1)
-	-	1	Neonatal severe primary hyperparathyroidism (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	14
DANN	Benign	0.55
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.054	T
MetaRNN	Benign	7.8e-7	T
MetaSVM	Benign	-0.94	T
PhyloP100		1.2
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.26	N
REVEL	Benign	0.24
Sift	Benign	1.0	T
Sift4G	Benign	0.85	T
Vest4		0.026
MPC		0.59
ClinPred		0.0033	T
GERP RS		5.8
Varity_R		0.057
gMVP		0.18
Mutation Taster		=99/1	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: rs1801726; hg19: chr3-122003832; COSMIC: COSV107356745;