3-122205537-G-T

Variant names:

• chr3-122205537-G-T
• rs7614486
• NM_000388.4:c.-243+21725G>T

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+21725G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.741 in 151,860 control chromosomes in the GnomAD database, including 42,022 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 0.74 (42022 hom., cov: 32)
• Consequence: CASR NM_000388.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.730
• Publications: 5 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=-0.78).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.816 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASR	NM_000388.4	c.-243+21725G>T		intron_variant	Intron 1 of 6	ENST00000639785.2	NP_000379.3
CASR	NM_001178065.2	c.-243+21008G>T		intron_variant	Intron 1 of 6		NP_001171536.2
CASR	XM_006713789.4	c.-243+21008G>T		intron_variant	Intron 1 of 6		XP_006713852.1
CASR	XM_047449065.1	c.-419+21008G>T		intron_variant	Intron 1 of 5		XP_047305021.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASR	ENST00000639785.2	c.-243+21725G>T		intron_variant	Intron 1 of 6	1	NM_000388.4	ENSP00000491584.2
CASR	ENST00000498619.4	c.-243+21008G>T		intron_variant	Intron 1 of 6	1		ENSP00000420194.1
CASR	ENST00000638421.1	c.-243+21008G>T		intron_variant	Intron 1 of 6	5		ENSP00000492190.1
CASR	ENST00000643573.1	n.98+21008G>T		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes AF: 0.741 AC: 112487 AN: 151744 Hom.: 41986 Cov.: 32

Gnomad AFR AF: 0.749

Gnomad AMI AF: 0.834

Gnomad AMR AF: 0.828

Gnomad ASJ AF: 0.766

Gnomad EAS AF: 0.461

Gnomad SAS AF: 0.491

Gnomad FIN AF: 0.736

Gnomad MID AF: 0.750

Gnomad NFE AF: 0.754

Gnomad OTH AF: 0.753

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

GnomAD4 genome AF: 0.741 AC: 112575 AN: 151860 Hom.: 42022 Cov.: 32 AF XY: 0.740 AC XY: 54955 AN XY: 74254

African (AFR) AF: 0.749 AC: 31039 AN: 41462

American (AMR) AF: 0.828 AC: 12653 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.766 AC: 2652 AN: 3464

East Asian (EAS) AF: 0.462 AC: 2384 AN: 5162

South Asian (SAS) AF: 0.491 AC: 2359 AN: 4802

European-Finnish (FIN) AF: 0.736 AC: 7751 AN: 10532

Middle Eastern (MID) AF: 0.755 AC: 222 AN: 294

European-Non Finnish (NFE) AF: 0.754 AC: 51180 AN: 67840

Other (OTH) AF: 0.745 AC: 1574 AN: 2112

Alfa AF: 0.746 Hom.: 5270

Bravo AF: 0.753

Asia WGS AF: 0.453 AC: 1580 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.1
DANN	Benign	0.71
PhyloP100		-0.73
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: rs7614486; hg19: chr3-121924384;