chr3-122254079-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_000388.4(CASR):c.-111C>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000189 in 912,410 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000098 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00021 ( 1 hom. )

Consequence

CASR
NM_000388.4 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 0.554

Publications

0 publications found

Variant links:

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, ClinGen, Labcorp Genetics (formerly Invitae)
familial hypocalciuric hypercalcemia 1
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Illumina, Orphanet, Genomics England PanelApp
neonatal severe primary hyperparathyroidism
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)
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

CASR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BP6

Variant 3-122254079-C-A is Benign according to our data. Variant chr3-122254079-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 342794.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000985 (15/152358) while in subpopulation EAS AF = 0.00289 (15/5194). AF 95% confidence interval is 0.00178. There are 0 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASR	NM_000388.4 link	c.-111C>A		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 7	ENST00000639785.2	NP_000379.3	P41180-1
CASR	NM_000388.4 link	c.-111C>A		5_prime_UTR_variant	Exon 2 of 7	ENST00000639785.2	NP_000379.3	P41180-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASR	ENST00000639785.2 link	c.-111C>A		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 7	1	NM_000388.4	ENSP00000491584.2		P41180-1
CASR	ENST00000639785.2 link	c.-111C>A		5_prime_UTR_variant	Exon 2 of 7	1	NM_000388.4	ENSP00000491584.2		P41180-1

Frequencies

GnomAD3 genomes

AF:

0.0000985

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00288

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000207

AC:

157

AN:

760052

Hom.:

Cov.:

AF XY:

0.000220

AC XY:

AN XY:

404940

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

20084

American (AMR)

AF:

0.00

AC:

AN:

43638

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21668

East Asian (EAS)

AF:

0.00426

AC:

156

AN:

36622

South Asian (SAS)

AF:

0.00

AC:

AN:

71686

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46548

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2796

European-Non Finnish (NFE)

AF:

0.00000208

AC:

AN:

479616

Other (OTH)

AF:

0.00

AC:

AN:

37394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000985

AC:

AN:

152358

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41568

American (AMR)

AF:

0.00

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00289

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68044

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000831

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal dominant hypocalcemia 1

Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Neonatal severe primary hyperparathyroidism

Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Familial hypocalciuric hypercalcemia 1

Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Familial hypoparathyroidism

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Benign

0.77

PhyloP100

0.55

PromoterAI

0.0028

Neutral

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

chr3-122254079-C-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over