chr3-122284910-G-T

Variant names:

• chr3-122284910-G-T
• rs1801725
• NM_000388.4:c.2956G>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000388.4(CASR):​c.2956G>T​(p.Ala986Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 1,614,034 control chromosomes in the GnomAD database, including 15,629 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A986D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.11 (1222 hom., cov: 33)
  • Exomes 𝑓: 0.13 (14407 hom.)
• Consequence: CASR NM_000388.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16 O:1
• Conservation: PhyloP100: 3.23
• Publications: 245 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, 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

ACMG classification

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 neonatal severe primary hyperparathyroidism, autosomal dominant hypocalcemia 1, familial hypocalciuric hypercalcemia 1, epilepsy, autosomal dominant hypocalcemia, epilepsy, idiopathic generalized, susceptibility to, 8.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0016186535).
• BP6: Variant 3-122284910-G-T is Benign according to our data. Variant chr3-122284910-G-T is described in ClinVar as Benign. ClinVar VariationId is 8349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

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.2956G>T	p.Ala986Ser	missense	Exon 7 of 7	NP_000379.3
	CASR	NM_001178065.2		c.2986G>T	p.Ala996Ser	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.2956G>T	p.Ala986Ser	missense	Exon 7 of 7	ENSP00000491584.2	P41180-1
	CASR	ENST00000498619.4	TSL:1	c.2986G>T	p.Ala996Ser	missense	Exon 7 of 7	ENSP00000420194.1	P41180-2
	CASR	ENST00000638421.1	TSL:5	c.2956G>T	p.Ala986Ser	missense	Exon 7 of 7	ENSP00000492190.1	P41180-1

Frequencies

GnomAD3 genomes AF: 0.110 AC: 16746 AN: 152080 Hom.: 1221 Cov.: 33

Gnomad AFR AF: 0.0350

Gnomad AMI AF: 0.0965

Gnomad AMR AF: 0.121

Gnomad ASJ AF: 0.263

Gnomad EAS AF: 0.0319

Gnomad SAS AF: 0.183

Gnomad FIN AF: 0.137

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.141

Gnomad OTH AF: 0.142

GnomAD2 exomes AF: 0.129 AC: 32291 AN: 251286 AF XY: 0.137

Gnomad AFR exome AF: 0.0332

Gnomad AMR exome AF: 0.0820

Gnomad ASJ exome AF: 0.259

Gnomad EAS exome AF: 0.0301

Gnomad FIN exome AF: 0.135

Gnomad NFE exome AF: 0.140

Gnomad OTH exome AF: 0.161

GnomAD4 exome AF: 0.134 AC: 195949 AN: 1461836 Hom.: 14407 Cov.: 73 AF XY: 0.138 AC XY: 100135 AN XY: 727212

African (AFR) AF: 0.0340 AC: 1139 AN: 33478

American (AMR) AF: 0.0868 AC: 3882 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.260 AC: 6790 AN: 26134

East Asian (EAS) AF: 0.0224 AC: 889 AN: 39700

South Asian (SAS) AF: 0.194 AC: 16713 AN: 86256

European-Finnish (FIN) AF: 0.135 AC: 7190 AN: 53416

Middle Eastern (MID) AF: 0.269 AC: 1552 AN: 5768

European-Non Finnish (NFE) AF: 0.134 AC: 149151 AN: 1111976

Other (OTH) AF: 0.143 AC: 8643 AN: 60394

GnomAD4 genome AF: 0.110 AC: 16743 AN: 152198 Hom.: 1222 Cov.: 33 AF XY: 0.111 AC XY: 8274 AN XY: 74416

African (AFR) AF: 0.0350 AC: 1453 AN: 41532

American (AMR) AF: 0.121 AC: 1858 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 912 AN: 3468

East Asian (EAS) AF: 0.0316 AC: 164 AN: 5188

South Asian (SAS) AF: 0.183 AC: 882 AN: 4822

European-Finnish (FIN) AF: 0.137 AC: 1448 AN: 10574

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.141 AC: 9563 AN: 67994

Other (OTH) AF: 0.141 AC: 298 AN: 2110

Alfa AF: 0.135 Hom.: 7743

Bravo AF: 0.104

TwinsUK AF: 0.131 AC: 487

ALSPAC AF: 0.130 AC: 501

ESP6500AA AF: 0.0406 AC: 179

ESP6500EA AF: 0.148 AC: 1272

ExAC AF: 0.127 AC: 15416

Asia WGS AF: 0.112 AC: 389 AN: 3478

EpiCase AF: 0.147

EpiControl AF: 0.159

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	1	Autosomal dominant hypocalcemia 1 (1)
-	-	1	Autosomal dominant hypocalcemia 1;C1809471:Familial hypocalciuric hypercalcemia (1)
-	-	1	Familial hypocalciuric hypercalcemia 1 (1)
-	-	1	Familial hypoparathyroidism (1)
-	-	1	Malignant tumor of breast (1)
-	-	1	Neonatal severe primary hyperparathyroidism (1)
-	-	1	Nephrolithiasis/nephrocalcinosis (1)
-	-	1	not provided (1)
-	-	-	Serum calcium level (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.098
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.8	L
PhyloP100		3.2
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.29
Sift	Benign	0.19	T
Sift4G	Benign	0.20	T
Polyphen		0.20	B
Vest4		0.029
MPC		0.56
ClinPred		0.0092	T
GERP RS		4.9
Varity_R		0.094
gMVP		0.21
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1801725; hg19: chr3-122003757; COSMIC: COSV56138925;