rs201990892

Variant names:

• chr3-122284967-G-A
• rs201990892
• NM_000388.4:c.3013G>A
• CASR p.Asp1005Asn

Your query was ambiguous. Multiple possible variants found:

• chr3-122284967-G-A
• chr3-122284967-G-C
• chr3-122284967-G-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 1P and 3B. PP2 BP4_Moderate BP6

The NM_000388.4(CASR):​c.3013G>A​(p.Asp1005Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000121 in 1,614,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1005H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: CASR NM_000388.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 7.24
• Publications: 10 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: Illumina, ClinGen, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• 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

ACMG classification

Our verdict: Likely_benign. The variant received -2 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=0.25029677).
• BP6: Variant 3-122284967-G-A is Benign according to our data. Variant chr3-122284967-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 420107.

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.3013G>A	p.Asp1005Asn	missense	Exon 7 of 7	NP_000379.3
	CASR	NM_001178065.2		c.3043G>A	p.Asp1015Asn	missense	Exon 7 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.3013G>A	p.Asp1005Asn	missense	Exon 7 of 7	ENSP00000491584.2	P41180-1
	CASR	ENST00000498619.4	TSL:1	c.3043G>A	p.Asp1015Asn	missense	Exon 7 of 7	ENSP00000420194.1	P41180-2
	CASR	ENST00000638421.1	TSL:5	c.3013G>A	p.Asp1005Asn	missense	Exon 7 of 7	ENSP00000492190.1	P41180-1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152188 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000597 AC: 15 AN: 251326 AF XY: 0.0000442

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000127 AC: 185 AN: 1461872 Hom.: 0 Cov.: 71 AF XY: 0.000138 AC XY: 100 AN XY: 727242

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000157 AC: 175 AN: 1112002

Other (OTH) AF: 0.0000993 AC: 6 AN: 60396

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152188 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74338

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000124 Hom.: 0

Bravo AF: 0.0000642

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

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

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.069
Eigen_PC	Benign	0.015
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.25	T
MetaSVM	Uncertain	0.097	D
MutationAssessor	Benign	1.6	L
PhyloP100		7.2
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.65	N
REVEL	Uncertain	0.35
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0090	D
Varity_R		0.11
gMVP		0.41
Mutation Taster		=2/98	disease causing

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

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

Other links and lift over

dbSNP: rs201990892;

hg19: chr3-122003814;

COSMIC: COSV99948386;