NM_000388.4:c.493-133T>C

Variant names:

• chr3-122261395-T-C
• rs3749207
• NM_000388.4:c.493-133T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000388.4(CASR):​c.493-133T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.646 in 814,398 control chromosomes in the GnomAD database, including 175,749 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.57 (26636 hom., cov: 32)
  • Exomes 𝑓: 0.66 (149113 hom.)
• Consequence: CASR NM_000388.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.472
• Publications: 4 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 3-122261395-T-C is Benign according to our data. Variant chr3-122261395-T-C is described in ClinVar as Benign. ClinVar VariationId is 1268856.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.704 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASR	NM_000388.4	c.493-133T>C		intron_variant	Intron 3 of 6	ENST00000639785.2	NP_000379.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASR	ENST00000639785.2	c.493-133T>C		intron_variant	Intron 3 of 6	1	NM_000388.4	ENSP00000491584.2
CASR	ENST00000498619.4	c.493-133T>C		intron_variant	Intron 3 of 6	1		ENSP00000420194.1
CASR	ENST00000638421.1	c.493-133T>C		intron_variant	Intron 3 of 6	5		ENSP00000492190.1
CASR	ENST00000490131.7	c.493-133T>C		intron_variant	Intron 2 of 4	5		ENSP00000418685.2

Frequencies

GnomAD3 genomes AF: 0.566 AC: 85964 AN: 151934 Hom.: 26638 Cov.: 32

Gnomad AFR AF: 0.295

Gnomad AMI AF: 0.545

Gnomad AMR AF: 0.606

Gnomad ASJ AF: 0.775

Gnomad EAS AF: 0.554

Gnomad SAS AF: 0.722

Gnomad FIN AF: 0.678

Gnomad MID AF: 0.763

Gnomad NFE AF: 0.681

Gnomad OTH AF: 0.625

GnomAD4 exome AF: 0.664 AC: 439915 AN: 662346 Hom.: 149113 AF XY: 0.673 AC XY: 241458 AN XY: 358764

African (AFR) AF: 0.291 AC: 5376 AN: 18484

American (AMR) AF: 0.574 AC: 24895 AN: 43364

Ashkenazi Jewish (ASJ) AF: 0.772 AC: 16181 AN: 20970

East Asian (EAS) AF: 0.565 AC: 20431 AN: 36174

South Asian (SAS) AF: 0.740 AC: 51433 AN: 69510

European-Finnish (FIN) AF: 0.676 AC: 26912 AN: 39840

Middle Eastern (MID) AF: 0.787 AC: 2052 AN: 2608

European-Non Finnish (NFE) AF: 0.679 AC: 269686 AN: 396954

Other (OTH) AF: 0.666 AC: 22949 AN: 34442

GnomAD4 genome AF: 0.566 AC: 85988 AN: 152052 Hom.: 26636 Cov.: 32 AF XY: 0.568 AC XY: 42201 AN XY: 74320

African (AFR) AF: 0.295 AC: 12213 AN: 41468

American (AMR) AF: 0.606 AC: 9267 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.775 AC: 2690 AN: 3470

East Asian (EAS) AF: 0.555 AC: 2864 AN: 5164

South Asian (SAS) AF: 0.724 AC: 3482 AN: 4810

European-Finnish (FIN) AF: 0.678 AC: 7157 AN: 10562

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

European-Non Finnish (NFE) AF: 0.681 AC: 46288 AN: 67968

Other (OTH) AF: 0.623 AC: 1313 AN: 2106

Alfa AF: 0.592 Hom.: 4147

Bravo AF: 0.547

Asia WGS AF: 0.613 AC: 2132 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	11
DANN	Benign	0.38
PhyloP100		0.47
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: rs3749207; hg19: chr3-121980242;