NM_000388.4:c.-137C>T

Variant names:

• chr3-122254053-C-T
• rs201074178
• NM_000388.4:c.-137C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_000388.4(CASR):​c.-137C>T 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 0.000138 in 841,044 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (1 hom.)
• Consequence: CASR NM_000388.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:4
• Conservation: PhyloP100: -0.521
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000148 (102/688802) while in subpopulation SAS AF = 0.000688 (48/69760). AF 95% confidence interval is 0.000533. There are 1 homozygotes in GnomAdExome4. There are 69 alleles in the male GnomAdExome4 subpopulation. Median coverage is 9. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.-137C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 7	NP_000379.3
	CASR	NM_000388.4	MANE Select	c.-137C>T		5_prime_UTR	Exon 2 of 7	NP_000379.3
	CASR	NM_001178065.2		c.-137C>T		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.-137C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 7	ENSP00000491584.2	P41180-1
	CASR	ENST00000498619.4	TSL:1	c.-137C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 7	ENSP00000420194.1	P41180-2
	CASR	ENST00000639785.2	TSL:1 MANE Select	c.-137C>T		5_prime_UTR	Exon 2 of 7	ENSP00000491584.2	P41180-1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152242 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000148 AC: 102 AN: 688802 Hom.: 1 Cov.: 9 AF XY: 0.000187 AC XY: 69 AN XY: 369752

African (AFR) AF: 0.0000534 AC: 1 AN: 18732

American (AMR) AF: 0.0000700 AC: 3 AN: 42836

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21138

East Asian (EAS) AF: 0.0000831 AC: 3 AN: 36118

South Asian (SAS) AF: 0.000688 AC: 48 AN: 69760

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40180

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2660

European-Non Finnish (NFE) AF: 0.000107 AC: 45 AN: 422298

Other (OTH) AF: 0.0000570 AC: 2 AN: 35080

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74380

African (AFR) AF: 0.0000965 AC: 4 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5206

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68054

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000110

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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	-0.83
CADD	Benign	12
DANN	Benign	0.36
PhyloP100		-0.52
PromoterAI		0.0023	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201074178; hg19: chr3-121972900;