3-122257203-CC-TA

Variant names:

• chr3-122257203-CC-TA
• NM_000388.4:c.308_309delCCinsTA
• CASR p.Thr103Ile

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_000388.4(CASR):c.308_309delCCinsTA (p.Thr103Ile) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.T103I: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 463947); 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: not found (cov: 32)
• Consequence: CASR NM_000388.4 missense
• Clinical Significance: Not reported in ClinVar
• 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 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (threshold 0.0001) — PM2 moderate.

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.308_309delCCinsTA p.Thr103Ile	missense	N/A	Prot: NP_000379.3
	CASR NM_001178065.2		c.308_309delCCinsTA p.Thr103Ile	missense	N/A	Prot: NP_001171536.2 UniProt:

CASR NM_000388.4

MANE Select

HGVSc / HGVSpc.308_309delCCinsTAp.Thr103Ile

Exon rankN/A

missense

Prot: NP_000379.3

CASR NM_001178065.2

HGVSc / HGVSpc.308_309delCCinsTAp.Thr103Ile

Exon rankN/A

missense

Prot: NP_001171536.2UniProt: P41180-2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CASR ENST00000639785.2	TSL:1MANE Select	c.308_309delCCinsTA p.Thr103Ile	missense	N/A	Prot: ENSP00000491584.2 UniProt:
	CASR ENST00000498619.4	TSL:1	c.308_309delCCinsTA p.Thr103Ile	missense	N/A	Prot: ENSP00000420194.1 UniProt:
	CASR ENST00000638421.1	TSL:5	c.308_309delCCinsTA p.Thr103Ile	missense	N/A	Prot: ENSP00000492190.1 UniProt:

CASR ENST00000639785.2

TSL:1MANE Select

HGVSc / HGVSpc.308_309delCCinsTAp.Thr103Ile

Exon rankN/A

missense

Prot: ENSP00000491584.2UniProt: P41180-1

CASR ENST00000498619.4

TSL:1

HGVSc / HGVSpc.308_309delCCinsTAp.Thr103Ile

Exon rankN/A

missense

Prot: ENSP00000420194.1UniProt: P41180-2

CASR ENST00000638421.1

TSL:5

HGVSc / HGVSpc.308_309delCCinsTAp.Thr103Ile

Exon rankN/A

missense

Prot: ENSP00000492190.1UniProt: 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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Uncertain	6.2

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

hg19: chr3-121976050;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar