chr3-122282024-C-T

Variant names:

• chr3-122282024-C-T
• rs4678174
• NM_000388.4:c.1609-89C>T

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.1609-89C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.656 in 1,586,760 control chromosomes in the GnomAD database, including 348,569 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (26503 hom., cov: 32)
  • Exomes 𝑓: 0.67 (322066 hom.)
• Consequence: CASR NM_000388.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.368
• Publications: 16 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=-0.74).
• BP6: Variant 3-122282024-C-T is Benign according to our data. Variant chr3-122282024-C-T is described in ClinVar as Benign. ClinVar VariationId is 1192651.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.704 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.1609-89C>T		intron	N/A	NP_000379.3
	CASR	NM_001178065.2		c.1609-59C>T		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.1609-89C>T		intron	N/A	ENSP00000491584.2	P41180-1
	CASR	ENST00000498619.4	TSL:1	c.1609-59C>T		intron	N/A	ENSP00000420194.1	P41180-2
	CASR	ENST00000638421.1	TSL:5	c.1609-89C>T		intron	N/A	ENSP00000492190.1	P41180-1

Frequencies

GnomAD3 genomes AF: 0.563 AC: 85609 AN: 151978 Hom.: 26505 Cov.: 32

Gnomad AFR AF: 0.285

Gnomad AMI AF: 0.545

Gnomad AMR AF: 0.605

Gnomad ASJ AF: 0.775

Gnomad EAS AF: 0.557

Gnomad SAS AF: 0.722

Gnomad FIN AF: 0.677

Gnomad MID AF: 0.763

Gnomad NFE AF: 0.681

Gnomad OTH AF: 0.625

GnomAD4 exome AF: 0.665 AC: 954660 AN: 1434662 Hom.: 322066 AF XY: 0.671 AC XY: 477952 AN XY: 712644

African (AFR) AF: 0.273 AC: 8986 AN: 32960

American (AMR) AF: 0.572 AC: 25387 AN: 44352

Ashkenazi Jewish (ASJ) AF: 0.773 AC: 19827 AN: 25644

East Asian (EAS) AF: 0.566 AC: 22247 AN: 39312

South Asian (SAS) AF: 0.739 AC: 62886 AN: 85150

European-Finnish (FIN) AF: 0.679 AC: 35908 AN: 52868

Middle Eastern (MID) AF: 0.779 AC: 4436 AN: 5698

European-Non Finnish (NFE) AF: 0.675 AC: 735330 AN: 1089292

Other (OTH) AF: 0.668 AC: 39653 AN: 59386

GnomAD4 genome AF: 0.563 AC: 85631 AN: 152098 Hom.: 26503 Cov.: 32 AF XY: 0.566 AC XY: 42040 AN XY: 74340

African (AFR) AF: 0.285 AC: 11816 AN: 41460

American (AMR) AF: 0.605 AC: 9242 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.775 AC: 2692 AN: 3472

East Asian (EAS) AF: 0.557 AC: 2875 AN: 5164

South Asian (SAS) AF: 0.724 AC: 3495 AN: 4828

European-Finnish (FIN) AF: 0.677 AC: 7162 AN: 10584

Middle Eastern (MID) AF: 0.738 AC: 217 AN: 294

European-Non Finnish (NFE) AF: 0.681 AC: 46317 AN: 67986

Other (OTH) AF: 0.623 AC: 1318 AN: 2114

Alfa AF: 0.598 Hom.: 5866

Bravo AF: 0.544

Asia WGS AF: 0.611 AC: 2124 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	6.9
DANN	Benign	0.76
PhyloP100		0.37
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: rs4678174; hg19: chr3-122000871; COSMIC: COSV56139987;