chr3-122257685-A-C

Variant names:

• chr3-122257685-A-C
• rs3749204
• NM_000388.4:c.492+298A>C

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-2 Likely Benign

-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). PM2BP4_Strong

The NM_000388.4(CASR):c.492+298A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CASR NM_000388.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.363
• Publications: 2 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: Likely_benign. 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.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).

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.492+298A>C	intron	Intron 3 of 6	Prot: NP_000379.3
	CASR NM_001178065.2		c.492+298A>C	intron	Intron 3 of 6	Prot: NP_001171536.2 UniProt:

CASR NM_000388.4

MANE Select

HGVSc / HGVSpc.492+298A>C

Exon rankIntron 3 of 6

intron

Prot: NP_000379.3

CASR NM_001178065.2

HGVSc / HGVSpc.492+298A>C

Exon rankIntron 3 of 6

intron

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.492+298A>C	intron	Intron 3 of 6	Prot: ENSP00000491584.2 UniProt:
	CASR ENST00000498619.4	TSL:1	c.492+298A>C	intron	Intron 3 of 6	Prot: ENSP00000420194.1 UniProt:
	CASR ENST00000638421.1	TSL:5	c.492+298A>C	intron	Intron 3 of 6	Prot: ENSP00000492190.1 UniProt:

CASR ENST00000639785.2

TSL:1MANE Select

HGVSc / HGVSpc.492+298A>C

Exon rankIntron 3 of 6

intron

Prot: ENSP00000491584.2UniProt: P41180-1

CASR ENST00000498619.4

TSL:1

HGVSc / HGVSpc.492+298A>C

Exon rankIntron 3 of 6

intron

Prot: ENSP00000420194.1UniProt: P41180-2

CASR ENST00000638421.1

TSL:5

HGVSc / HGVSpc.492+298A>C

Exon rankIntron 3 of 6

intron

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 4 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome Warning	AF: 0.00	AC:0	Hom:0	AN:127224	Cov:0
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:2430	AN:23486	Cov:

Showing 4 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	1.7
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.8
DANN	Benign	0.88
GPN-Star LLR	N/A	-0.087
GPN-Star score	N/A	0.087
PhyloP100	Benign	-0.36

Showing 7 of 7 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.020
SpliceAI score (max)	Benign	0.020	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.

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

dbSNP: rs3749204;

hg19: chr3-121976532;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar