chr3-122196010-G-A

Variant names:

• chr3-122196010-G-A
• rs6802749
• NM_000388.4:c.-243+12198G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000388.4(CASR):​c.-243+12198G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.175 in 152,064 control chromosomes in the GnomAD database, including 2,407 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.17 (2407 hom., cov: 32)
• Consequence: CASR NM_000388.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.189
• Publications: 3 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, ClinGen, Labcorp Genetics (formerly Invitae)
• familial hypocalciuric hypercalcemia 1

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

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.21 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASR	NM_000388.4	MANE Select	c.-243+12198G>A		intron	N/A	NP_000379.3
	CASR	NM_001178065.2		c.-243+11481G>A		intron	N/A	NP_001171536.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASR	ENST00000639785.2	TSL:1 MANE Select	c.-243+12198G>A		intron	N/A	ENSP00000491584.2
	CASR	ENST00000498619.4	TSL:1	c.-243+11481G>A		intron	N/A	ENSP00000420194.1
	CASR	ENST00000638421.1	TSL:5	c.-243+11481G>A		intron	N/A	ENSP00000492190.1

Frequencies

GnomAD3 genomes AF: 0.175 AC: 26581 AN: 151946 Hom.: 2400 Cov.: 32

Gnomad AFR AF: 0.213

Gnomad AMI AF: 0.179

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.172

Gnomad EAS AF: 0.0302

Gnomad SAS AF: 0.146

Gnomad FIN AF: 0.196

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.176

Gnomad OTH AF: 0.170

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.175 AC: 26594 AN: 152064 Hom.: 2407 Cov.: 32 AF XY: 0.170 AC XY: 12664 AN XY: 74336

African (AFR) AF: 0.213 AC: 8845 AN: 41464

American (AMR) AF: 0.112 AC: 1711 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 595 AN: 3466

East Asian (EAS) AF: 0.0303 AC: 157 AN: 5184

South Asian (SAS) AF: 0.146 AC: 704 AN: 4824

European-Finnish (FIN) AF: 0.196 AC: 2073 AN: 10574

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.176 AC: 11947 AN: 67958

Other (OTH) AF: 0.167 AC: 353 AN: 2110

Alfa AF: 0.157 Hom.: 1071

Bravo AF: 0.171

Asia WGS AF: 0.0800 AC: 280 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.6
DANN	Benign	0.76
PhyloP100		-0.19
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: rs6802749; hg19: chr3-121914857;