NM_000388.4:c.-243+26023T>C

Variant names:

• chr3-122209835-T-C
• rs7638770
• NM_000388.4:c.-243+26023T>C

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+26023T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.725 in 152,066 control chromosomes in the GnomAD database, including 40,197 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 0.72 (40197 hom., cov: 31)
• Consequence: CASR NM_000388.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.306
• Publications: 1 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.809 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.-243+26023T>C		intron	N/A	NP_000379.3
	CASR	NM_001178065.2		c.-243+25306T>C		intron	N/A	NP_001171536.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASR	ENST00000639785.2	TSL:1 MANE Select	c.-243+26023T>C		intron	N/A	ENSP00000491584.2
	CASR	ENST00000498619.4	TSL:1	c.-243+25306T>C		intron	N/A	ENSP00000420194.1
	CASR	ENST00000638421.1	TSL:5	c.-243+25306T>C		intron	N/A	ENSP00000492190.1

Frequencies

GnomAD3 genomes AF: 0.725 AC: 110146 AN: 151948 Hom.: 40169 Cov.: 31

Gnomad AFR AF: 0.674

Gnomad AMI AF: 0.834

Gnomad AMR AF: 0.820

Gnomad ASJ AF: 0.765

Gnomad EAS AF: 0.467

Gnomad SAS AF: 0.649

Gnomad FIN AF: 0.735

Gnomad MID AF: 0.758

Gnomad NFE AF: 0.754

Gnomad OTH AF: 0.739

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

GnomAD4 genome AF: 0.725 AC: 110224 AN: 152066 Hom.: 40197 Cov.: 31 AF XY: 0.727 AC XY: 54045 AN XY: 74354

African (AFR) AF: 0.674 AC: 27943 AN: 41438

American (AMR) AF: 0.821 AC: 12535 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.765 AC: 2653 AN: 3468

East Asian (EAS) AF: 0.467 AC: 2423 AN: 5184

South Asian (SAS) AF: 0.649 AC: 3127 AN: 4820

European-Finnish (FIN) AF: 0.735 AC: 7770 AN: 10578

Middle Eastern (MID) AF: 0.764 AC: 223 AN: 292

European-Non Finnish (NFE) AF: 0.754 AC: 51245 AN: 67990

Other (OTH) AF: 0.732 AC: 1546 AN: 2112

Alfa AF: 0.729 Hom.: 4970

Bravo AF: 0.731

Asia WGS AF: 0.543 AC: 1890 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.1
DANN	Benign	0.72
PhyloP100		0.31
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: rs7638770; hg19: chr3-121928682;