Genetic Variant NM_000388.4:c.1775A>G (chr3-122283729-A-G) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_000388.4(CASR):c.1775A>G(p.Asn592Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00109 in 1,614,178 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N592D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0017 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 33 hom. )

Consequence

CASR
NM_000388.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 5.05

Publications

14 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, Labcorp Genetics (formerly Invitae), ClinGen
familial hypocalciuric hypercalcemia 1
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Illumina, Orphanet, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
neonatal severe primary hyperparathyroidism
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, 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 -19 ACMG points.

PP2

Missense variant in the CASR gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 114 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 3.1237 (above the threshold of 3.09). Trascript score misZ: 4.8257 (above the threshold of 3.09). GenCC associations: The gene is linked to autosomal dominant hypocalcemia, familial hypocalciuric hypercalcemia 1, neonatal severe primary hyperparathyroidism, autosomal dominant hypocalcemia 1, epilepsy, epilepsy, idiopathic generalized, susceptibility to, 8.

BP4

Computational evidence support a benign effect (MetaRNN=0.008114517).

BP6

Variant 3-122283729-A-G is Benign according to our data. Variant chr3-122283729-A-G is described in ClinVar as Benign. ClinVar VariationId is 237760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00165 (252/152312) while in subpopulation EAS AF = 0.0396 (205/5178). AF 95% confidence interval is 0.0352. There are 3 homozygotes in GnomAd4. There are 127 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AD,AR gene

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASR	NM_000388.4	MANE Select	c.1775A>G	p.Asn592Ser	missense	Exon 7 of 7	NP_000379.3
	CASR	NM_001178065.2		c.1805A>G	p.Asn602Ser	missense	Exon 7 of 7	NP_001171536.2	P41180-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CASR	ENST00000639785.2	TSL:1 MANE Select	c.1775A>G	p.Asn592Ser	missense	Exon 7 of 7	ENSP00000491584.2	P41180-1
CASR	ENST00000498619.4	TSL:1	c.1805A>G	p.Asn602Ser	missense	Exon 7 of 7	ENSP00000420194.1	P41180-2
CASR	ENST00000638421.1	TSL:5	c.1775A>G	p.Asn592Ser	missense	Exon 7 of 7	ENSP00000492190.1	P41180-1

Frequencies

GnomAD3 genomes

AF:

0.00166

AC:

253

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000555

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0397

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.00363

AC:

912

AN:

251458

AF XY:

0.00324

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.00107

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0458

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000615

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00103

AC:

1500

AN:

1461866

Hom.:

Cov.:

AF XY:

0.000960

AC XY:

698

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33478

American (AMR)

AF:

0.000961

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0299

AC:

1186

AN:

39698

South Asian (SAS)

AF:

0.000267

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000621

AC:

AN:

1111996

Other (OTH)

AF:

0.00285

AC:

172

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

191

287

382

478

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00165

AC:

252

AN:

152312

Hom.:

Cov.:

AF XY:

0.00171

AC XY:

127

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.000553

AC:

AN:

41566

American (AMR)

AF:

0.000588

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.0396

AC:

205

AN:

5178

South Asian (SAS)

AF:

0.00104

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68028

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000962

Hom.:

Bravo

AF:

0.00166

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00330

AC:

400

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Autosomal dominant hypocalcemia 1 (1)

Familial hypocalciuric hypercalcemia 1 (1)

Familial hypocalciuric hypercalcemia;C3715128:Autosomal dominant hypocalcemia 1 (1)

Familial hypoparathyroidism (1)

Neonatal severe primary hyperparathyroidism (1)

Nephrolithiasis/nephrocalcinosis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.87

Eigen

Benign

0.084

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.86

MetaRNN

Benign

0.0081

MetaSVM

Uncertain

0.041

MutationAssessor

Uncertain

2.4

PhyloP100

5.1

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-3.7

REVEL

Uncertain

0.45

Sift

Benign

0.13

Sift4G

Benign

0.097

Polyphen

0.13

Vest4

0.27

MVP

0.93

MPC

0.48

ClinPred

0.033

GERP RS

4.8

Varity_R

0.48

gMVP

0.94

Mutation Taster

=98/2

polymorphism

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over