NM_000388.4:c.2669G>A

Variant names:

• chr3-122284623-G-A
• rs567996888
• NM_000388.4:c.2669G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM1 PP2 BP4

The NM_000388.4(CASR):​c.2669G>A​(p.Arg890His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,614,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R890C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: CASR NM_000388.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.59
• Publications: 6 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: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 20 uncertain in NM_000388.4
• 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=0.33874032).

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.2669G>A	p.Arg890His	missense	Exon 7 of 7	NP_000379.3
	CASR	NM_001178065.2		c.2699G>A	p.Arg900His	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.2669G>A	p.Arg890His	missense	Exon 7 of 7	ENSP00000491584.2	P41180-1
	CASR	ENST00000498619.4	TSL:1	c.2699G>A	p.Arg900His	missense	Exon 7 of 7	ENSP00000420194.1	P41180-2
	CASR	ENST00000638421.1	TSL:5	c.2669G>A	p.Arg890His	missense	Exon 7 of 7	ENSP00000492190.1	P41180-1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250664 AF XY: 0.00

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461696 Hom.: 0 Cov.: 70 AF XY: 0.0000110 AC XY: 8 AN XY: 727168

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111954

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152332 Hom.: 0 Cov.: 33 AF XY: 0.0000268 AC XY: 2 AN XY: 74492

African (AFR) AF: 0.0000240 AC: 1 AN: 41582

American (AMR) AF: 0.0000654 AC: 1 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Familial hypocalciuric hypercalcemia 1;C1832615:Neonatal severe primary hyperparathyroidism;C2752062:Epilepsy, idiopathic generalized, susceptibility to, 8;C3715128:Autosomal dominant hypocalcemia 1 (1)
-	1	-	Familial hypocalciuric hypercalcemia;C3715128:Autosomal dominant hypocalcemia 1 (1)
-	1	-	Nephrolithiasis/nephrocalcinosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	0.0054	T
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.37	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.098	D
MetaRNN	Benign	0.34	T
MetaSVM	Uncertain	0.29	D
MutationAssessor	Benign	1.8	L
PhyloP100		7.6
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.94	N
REVEL	Uncertain	0.45
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.98	D
Vest4		0.31
MutPred		0.32		Loss of helix (P = 0.0123)
MVP		0.96
MPC		1.5
ClinPred		0.90	D
GERP RS		5.9
Varity_R		0.34
gMVP		0.65
Mutation Taster		=60/40	polymorphism

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: rs567996888; hg19: chr3-122003470; COSMIC: COSV56142012;