rs2270916

Variant names:

• chr3-122282252-T-C
• rs2270916
• NM_000388.4:c.1732+16T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000388.4(CASR):​c.1732+16T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.135 in 1,613,346 control chromosomes in the GnomAD database, including 17,374 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1359 hom., cov: 32)
  • Exomes 𝑓: 0.14 (16015 hom.)
• Consequence: CASR NM_000388.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.75
• Publications: 24 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 3-122282252-T-C is Benign according to our data. Variant chr3-122282252-T-C is described in ClinVar as Benign. ClinVar VariationId is 257605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.384 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.1732+16T>C		intron	N/A	NP_000379.3
	CASR	NM_001178065.2		c.1762+16T>C		intron	N/A	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.1732+16T>C		intron	N/A	ENSP00000491584.2	P41180-1
	CASR	ENST00000498619.4	TSL:1	c.1762+16T>C		intron	N/A	ENSP00000420194.1	P41180-2
	CASR	ENST00000638421.1	TSL:5	c.1732+16T>C		intron	N/A	ENSP00000492190.1	P41180-1

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17650 AN: 152104 Hom.: 1362 Cov.: 32

Gnomad AFR AF: 0.0616

Gnomad AMI AF: 0.307

Gnomad AMR AF: 0.0947

Gnomad ASJ AF: 0.0825

Gnomad EAS AF: 0.399

Gnomad SAS AF: 0.0729

Gnomad FIN AF: 0.128

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.115

GnomAD2 exomes AF: 0.130 AC: 32638 AN: 251462 AF XY: 0.126

Gnomad AFR exome AF: 0.0600

Gnomad AMR exome AF: 0.0823

Gnomad ASJ exome AF: 0.0805

Gnomad EAS exome AF: 0.401

Gnomad FIN exome AF: 0.125

Gnomad NFE exome AF: 0.134

Gnomad OTH exome AF: 0.125

GnomAD4 exome AF: 0.137 AC: 200715 AN: 1461126 Hom.: 16015 Cov.: 32 AF XY: 0.134 AC XY: 97454 AN XY: 726880

African (AFR) AF: 0.0579 AC: 1939 AN: 33474

American (AMR) AF: 0.0823 AC: 3681 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0810 AC: 2115 AN: 26124

East Asian (EAS) AF: 0.395 AC: 15676 AN: 39676

South Asian (SAS) AF: 0.0630 AC: 5434 AN: 86228

European-Finnish (FIN) AF: 0.124 AC: 6610 AN: 53376

Middle Eastern (MID) AF: 0.0851 AC: 489 AN: 5744

European-Non Finnish (NFE) AF: 0.141 AC: 157254 AN: 1111430

Other (OTH) AF: 0.125 AC: 7517 AN: 60366

GnomAD4 genome AF: 0.116 AC: 17642 AN: 152220 Hom.: 1359 Cov.: 32 AF XY: 0.117 AC XY: 8712 AN XY: 74416

African (AFR) AF: 0.0614 AC: 2550 AN: 41544

American (AMR) AF: 0.0945 AC: 1445 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0825 AC: 286 AN: 3468

East Asian (EAS) AF: 0.399 AC: 2063 AN: 5176

South Asian (SAS) AF: 0.0729 AC: 351 AN: 4812

European-Finnish (FIN) AF: 0.128 AC: 1361 AN: 10612

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.133 AC: 9031 AN: 67996

Other (OTH) AF: 0.116 AC: 244 AN: 2112

Alfa AF: 0.111 Hom.: 239

Bravo AF: 0.115

Asia WGS AF: 0.180 AC: 624 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.30
DANN	Benign	0.75
PhyloP100		-1.8
Mutation Taster		=100/0	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: rs2270916; hg19: chr3-122001099; COSMIC: COSV56138050;