3-122194523-G-T

Variant names:

• chr3-122194523-G-T
• rs937627
• NM_000388.4:c.-243+10711G>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+10711G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.202 in 151,892 control chromosomes in the GnomAD database, including 3,927 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 0.20 (3927 hom., cov: 31)
• Consequence: CASR NM_000388.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.272
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.387 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASR	NM_000388.4	c.-243+10711G>T		intron_variant	Intron 1 of 6	ENST00000639785.2	NP_000379.3
CASR	NM_001178065.2	c.-243+9994G>T		intron_variant	Intron 1 of 6		NP_001171536.2
CASR	XM_006713789.4	c.-243+9994G>T		intron_variant	Intron 1 of 6		XP_006713852.1
CASR	XM_047449065.1	c.-419+9994G>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+10711G>T		intron_variant	Intron 1 of 6	1	NM_000388.4	ENSP00000491584.2
CASR	ENST00000498619.4	c.-243+9994G>T		intron_variant	Intron 1 of 6	1		ENSP00000420194.1
CASR	ENST00000638421.1	c.-243+9994G>T		intron_variant	Intron 1 of 6	5		ENSP00000492190.1
CASR	ENST00000643573.1	n.98+9994G>T		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes AF: 0.202 AC: 30708 AN: 151774 Hom.: 3914 Cov.: 31

Gnomad AFR AF: 0.0846

Gnomad AMI AF: 0.205

Gnomad AMR AF: 0.395

Gnomad ASJ AF: 0.157

Gnomad EAS AF: 0.362

Gnomad SAS AF: 0.163

Gnomad FIN AF: 0.218

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.221

Gnomad OTH AF: 0.208

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

GnomAD4 genome AF: 0.202 AC: 30741 AN: 151892 Hom.: 3927 Cov.: 31 AF XY: 0.208 AC XY: 15407 AN XY: 74246

African (AFR) AF: 0.0849 AC: 3516 AN: 41430

American (AMR) AF: 0.396 AC: 6043 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.157 AC: 541 AN: 3454

East Asian (EAS) AF: 0.363 AC: 1866 AN: 5144

South Asian (SAS) AF: 0.164 AC: 787 AN: 4800

European-Finnish (FIN) AF: 0.218 AC: 2300 AN: 10552

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.221 AC: 15011 AN: 67930

Other (OTH) AF: 0.207 AC: 435 AN: 2106

Alfa AF: 0.216 Hom.: 5154

Bravo AF: 0.216

Asia WGS AF: 0.200 AC: 694 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.78
DANN	Benign	0.72
PhyloP100		-0.27
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: rs937627; hg19: chr3-121913370;