rs201098532

Variant names:

• chr3-122254079-C-A
• rs201098532
• NM_000388.4:c.-111C>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_000388.4(CASR):​c.-111C>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000189 in 912,410 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (1 hom.)
• Consequence: CASR NM_000388.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 0.554
• Publications: 0 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, Labcorp Genetics (formerly Invitae), ClinGen
• familial hypocalciuric hypercalcemia 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Illumina, Orphanet, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• neonatal severe primary hyperparathyroidism

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 3-122254079-C-A is Benign according to our data. Variant chr3-122254079-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 342794.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000985 (15/152358) while in subpopulation EAS AF = 0.00289 (15/5194). AF 95% confidence interval is 0.00178. There are 0 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.-111C>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 7	NP_000379.3
	CASR	NM_000388.4	MANE Select	c.-111C>A		5_prime_UTR	Exon 2 of 7	NP_000379.3
	CASR	NM_001178065.2		c.-111C>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 7	NP_001171536.2	P41180-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASR	ENST00000639785.2	TSL:1 MANE Select	c.-111C>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 7	ENSP00000491584.2	P41180-1
	CASR	ENST00000498619.4	TSL:1	c.-111C>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 7	ENSP00000420194.1	P41180-2
	CASR	ENST00000639785.2	TSL:1 MANE Select	c.-111C>A		5_prime_UTR	Exon 2 of 7	ENSP00000491584.2	P41180-1

Frequencies

GnomAD3 genomes AF: 0.0000985 AC: 15 AN: 152240 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00288

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000207 AC: 157 AN: 760052 Hom.: 1 Cov.: 10 AF XY: 0.000220 AC XY: 89 AN XY: 404940

African (AFR) AF: 0.00 AC: 0 AN: 20084

American (AMR) AF: 0.00 AC: 0 AN: 43638

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21668

East Asian (EAS) AF: 0.00426 AC: 156 AN: 36622

South Asian (SAS) AF: 0.00 AC: 0 AN: 71686

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46548

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2796

European-Non Finnish (NFE) AF: 0.00000208 AC: 1 AN: 479616

Other (OTH) AF: 0.00 AC: 0 AN: 37394

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152358 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74508

African (AFR) AF: 0.00 AC: 0 AN: 41568

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00289 AC: 15 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000831

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal dominant hypocalcemia 1 (1)
-	1	-	Familial hypocalciuric hypercalcemia 1 (1)
-	-	1	Familial hypoparathyroidism (1)
-	1	-	Neonatal severe primary hyperparathyroidism (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	13
DANN	Benign	0.77
PhyloP100		0.55
PromoterAI		0.0028	Neutral

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: rs201098532; hg19: chr3-121972926;