rs199734455

Variant names:

• chr3-122257203-C-T
• rs199734455
• NM_000388.4:c.308C>T
• CASR p.Thr103Ile

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+1 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 1 classification points (ACMG Germline Pathogenicity v2019). PP3_ModerateBP6

The NM_000388.4(CASR):c.308C>T (p.Thr103Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000142 (AC=23) in the gnomAD database across 1,614,196 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000157. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (no review stars). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.T103S: Uncertain_significance (ClinVar VariationId 4788818, 1 star); p.T103= (synonymous): Likely_benign (ClinVar VariationId 1727556, 2 stars); p.T103= (synonymous): Likely_benign (ClinVar VariationId 532631, 2 stars)

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: CASR NM_000388.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 6.16
• 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, Illumina, ClinGen
• neonatal severe primary hyperparathyroidism

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• 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

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 1 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).
	BP6Reputable source reports benign		ClinVar 0-star benign — supporting (BP6); ClinVar germline classification: Benign/Likely Benign, 0 star(s).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000388.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASR	NM_000388.4	MANE Select	c.308C>T	p.Thr103Ile	missense	Exon 3 of 7	NP_000379.3
	CASR	NM_001178065.2		c.308C>T	p.Thr103Ile	missense	Exon 3 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.308C>T	p.Thr103Ile	missense	Exon 3 of 7	ENSP00000491584.2	P41180-1
	CASR	ENST00000498619.4	TSL:1	c.308C>T	p.Thr103Ile	missense	Exon 3 of 7	ENSP00000420194.1	P41180-2
	CASR	ENST00000638421.1	TSL:5	c.308C>T	p.Thr103Ile	missense	Exon 3 of 7	ENSP00000492190.1	P41180-1

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000460	AC:7	Hom:0	AN:152198	Cov:32
GnomAD2 exomes	AF: 0.0000159	AC:4	Hom:	AN:251424	Cov:
GnomAD4 exome	AF: 0.0000109	AC:16	Hom:0	AN:1461880	Cov:33
GnomAD4 genome	AF: 0.0000460	AC:7	Hom:0	AN:152316	Cov:32
TOPMed (Bravo)	AF: 0.0000378	AC:10	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000343	AC:7	Hom:0	AN:204022	Cov:
Local & regional cohorts 2 sources Population-specific and national genomic databases
GenomeAsia100K	AF: 0.000289	AC:1	Hom:	AN:3478	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0000160	AC:2	Hom:0	AN:122784	Cov:

Showing 8 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.00	0	41958	0.0000150	1	66888
SCHEMA(Schizophrenia)	0.0000177	2	113020	0.00000525	1	190328

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Familial hypocalciuric hypercalcemia 1;C1832615:Neonatal severe primary hyperparathyroidism;C2752062:Epilepsy, idiopathic generalized, susceptibility to, 8;C3715128:Autosomal dominant hypocalcemia 1 (1)
-	-	1	Familial hypocalciuric hypercalcemia;C3715128:Autosomal dominant hypocalcemia 1 (1)
-	1	-	Nephrolithiasis/nephrocalcinosis (1)
-	1	-	not provided (1)
-	-	1	not specified (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	30
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.97	D
FuncVEP CTI	Pathogenic	0.86
GPN-Star LLR	N/A	-9.7
GPN-Star score	N/A	9.7
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Uncertain	0.64	D
Mutation Taster	N/A	33/67	disease causing
MutationAssessor	Benign	1.9	M
PhyloP100	Uncertain	6.2
popEVE	Benign	-3.6
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.064	T
Varity_R	N/A	0.84
VESM-3B	Benign	-8.7

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.010	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs199734455;

hg19: chr3-121976050;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar