3-122284198-G-C

Position:

• chr3-122284198-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000388.4(CASR):​c.2244G>C​(p.Pro748=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.995 in 1,614,012 control chromosomes in the GnomAD database, including 799,557 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P748P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.97 (72351 hom., cov: 32)
  • Exomes 𝑓: 1.0 (727206 hom.)
• Consequence: CASR NM_000388.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.53

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 3-122284198-G-C is Benign according to our data. Variant chr3-122284198-G-C is described in ClinVar as [Benign]. Clinvar id is 166798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-122284198-G-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.53 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASR	NM_000388.4	c.2244G>C	p.Pro748=	synonymous_variant	7/7	ENST00000639785.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASR	ENST00000639785.2	c.2244G>C	p.Pro748=	synonymous_variant	7/7	1	NM_000388.4	P1
CASR	ENST00000498619.4	c.2274G>C	p.Pro758=	synonymous_variant	7/7	1
CASR	ENST00000638421.1	c.2244G>C	p.Pro748=	synonymous_variant	7/7	5		P1
CASR	ENST00000490131.7	c.2013G>C	p.Pro671=	synonymous_variant	5/5	5

Frequencies

GnomAD3 genomes AF: 0.974 AC: 148171 AN: 152160 Hom.: 72296 Cov.: 32

Gnomad AFR AF: 0.909

Gnomad AMI AF: 0.998

Gnomad AMR AF: 0.991

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.991

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.980

GnomAD3 exomes AF: 0.993 AC: 248891 AN: 250560 Hom.: 123700 AF XY: 0.995 AC XY: 134961 AN XY: 135594

Gnomad AFR exome AF: 0.907

Gnomad AMR exome AF: 0.996

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.998

GnomAD4 exome AF: 0.997 AC: 1457903 AN: 1461734 Hom.: 727206 Cov.: 69 AF XY: 0.998 AC XY: 725567 AN XY: 727178

Gnomad4 AFR exome AF: 0.907

Gnomad4 AMR exome AF: 0.995

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.994

GnomAD4 genome AF: 0.974 AC: 148284 AN: 152278 Hom.: 72351 Cov.: 32 AF XY: 0.976 AC XY: 72653 AN XY: 74468

Gnomad4 AFR AF: 0.909

Gnomad4 AMR AF: 0.991

Gnomad4 ASJ AF: 1.00

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 1.00

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 1.00

Gnomad4 OTH AF: 0.981

Alfa AF: 0.957 Hom.: 47605

Bravo AF: 0.971

Asia WGS AF: 0.993 AC: 3455 AN: 3478

EpiCase AF: 1.00

EpiControl AF: 1.00

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 22, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Autosomal dominant hypocalcemia 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Familial hypocalciuric hypercalcemia 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Neonatal severe primary hyperparathyroidism Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Autosomal dominant hypocalcemia 1;C1809471:Familial hypocalciuric hypercalcemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.66
DANN	Benign	0.71

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: rs2036400; hg19: chr3-122003045;