chr3-122254190-A-G

Position:

• chr3-122254190-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_000388.4(CASR):​c.1A>G​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CASR NM_000388.4 start_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.28

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 Pathogenic. Variant got 14 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_000388.4 (CASR) was described as [Pathogenic] in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-122254190-A-G is Pathogenic according to our data. Variant chr3-122254190-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1321411.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASR	NM_000388.4	c.1A>G	p.Met1?	start_lost	2/7	ENST00000639785.2	NP_000379.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASR	ENST00000639785.2	c.1A>G	p.Met1?	start_lost	2/7	1	NM_000388.4	ENSP00000491584.2
CASR	ENST00000498619.4	c.1A>G	p.Met1?	start_lost	2/7	1		ENSP00000420194.1
CASR	ENST00000638421.1	c.1A>G	p.Met1?	start_lost	2/7	5		ENSP00000492190.1
CASR	ENST00000490131.7	c.1A>G	p.Met1?	start_lost	1/5	5		ENSP00000418685.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial hypocalciuric hypercalcemia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 27, 2024

Variant summary: CASR c.1A>G (p.Met1Val) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. The variant is predicted to disrupt the original Kozak sequence (AXXATGG), altering the protein start site. Computational analysis using a program that predicts start sites identified five potential Kozak sequences: three upstream and one downstream of the original ATG site, which change the protein reading frame and create short sequences with a stop codon, and another downstream in-frame start codon in exon 3 (Met74) 222 bp downstream (PMID 17121537). Multiple pathogenic/likely pathogenic start codon variants have been reported (c.2T>C: LP in our lab, c.2T>G: PATH/ClinVar, c.1A>C: LP/ClinVar), and between the current variant and Met74, multiple pathogenic missense variants have been reported at our lab (p.Ser53Pro, p.Pro55Leu, p.Arg66Cys, p.Arg69His et al). The variant was absent in 251304 control chromosomes. To our knowledge, no occurrence of c.1A>G in individuals affected with Familial Hypocalciuric Hypercalcemia and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 1321411). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.41	T;T;.;.
Eigen	Benign	0.036
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.90	.;D;D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Uncertain	0.099	D
PROVEAN	Benign	-0.91	.;.;N;N
REVEL	Uncertain	0.64
Sift	Uncertain	0.0050	.;.;D;D
Sift4G	Uncertain	0.014	.;.;D;D
Polyphen		0.012	B;B;.;.
Vest4		0.67, 0.69
MutPred		0.84		Loss of glycosylation at S5 (P = 0.0332);Loss of glycosylation at S5 (P = 0.0332);Loss of glycosylation at S5 (P = 0.0332);Loss of glycosylation at S5 (P = 0.0332);
MVP		0.94
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.66
gMVP		0.78

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-121973037;