3-122258435-G-T

Variant names:

• chr3-122258435-G-T
• rs10934578
• NM_000388.4:c.492+1048G>T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000388.4(CASR):​c.492+1048G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.31 in 139,012 control chromosomes in the GnomAD database, including 7,364 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 0.31 (7364 hom., cov: 26)
• Consequence: CASR NM_000388.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0640

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.539 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASR	NM_000388.4	c.492+1048G>T		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.492+1048G>T		intron_variant	Intron 3 of 6	1	NM_000388.4	ENSP00000491584.2
CASR	ENST00000498619.4	c.492+1048G>T		intron_variant	Intron 3 of 6	1		ENSP00000420194.1
CASR	ENST00000638421.1	c.492+1048G>T		intron_variant	Intron 3 of 6	5		ENSP00000492190.1
CASR	ENST00000490131.7	c.492+1048G>T		intron_variant	Intron 2 of 4	5		ENSP00000418685.2

Frequencies

GnomAD3 genomes AF: 0.310 AC: 43088 AN: 138928 Hom.: 7355 Cov.: 26

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.167

Gnomad AMR AF: 0.415

Gnomad ASJ AF: 0.512

Gnomad EAS AF: 0.556

Gnomad SAS AF: 0.512

Gnomad FIN AF: 0.362

Gnomad MID AF: 0.519

Gnomad NFE AF: 0.334

Gnomad OTH AF: 0.363

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

GnomAD4 genome AF: 0.310 AC: 43119 AN: 139012 Hom.: 7364 Cov.: 26 AF XY: 0.318 AC XY: 21309 AN XY: 66948

Gnomad4 AFR AF: 0.133

Gnomad4 AMR AF: 0.415

Gnomad4 ASJ AF: 0.512

Gnomad4 EAS AF: 0.557

Gnomad4 SAS AF: 0.514

Gnomad4 FIN AF: 0.362

Gnomad4 NFE AF: 0.334

Gnomad4 OTH AF: 0.365

Alfa AF: 0.326 Hom.: 11624

Bravo AF: 0.287

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.6
DANN	Benign	0.53

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

Publications

LitVar

Other links and lift over

dbSNP: rs10934578; hg19: chr3-121977282; COSMIC: COSV56141790; COSMIC: COSV56141790;