rs751668850

Variant names:

• chr6-10874054-C-A
• rs751668850
• NM_004752.4:c.1462G>T

Your query was ambiguous. Multiple possible variants found:

• chr6-10874054-C-A
• chr6-10874054-C-T
• chr6-10874054-C-G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_004752.4(GCM2):​c.1462G>T​(p.Ala488Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000015 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A488T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: GCM2 NM_004752.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.304
• Publications: 4 publications found

Genes affected

GCM2 (HGNC:4198): (glial cells missing transcription factor 2) This gene is a homolog of the Drosophila glial cells missing gene, which is thought to act as a binary switch between neuronal and glial cell determination. The protein encoded by this gene contains a conserved N-terminal GCM motif that has DNA-binding activity. The protein is a transcription factor that acts as a master regulator of parathyroid development. It has been suggested that this transcription factor might mediate the effect of calcium on parathyroid hormone expression and secretion in parathyroid cells. Mutations in this gene are associated with hypoparathyroidism. [provided by RefSeq, Jul 2008]

GCM2 Gene-Disease associations (from GenCC):

• hypoparathyroidism, familial isolated, 2

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• familial isolated hyperparathyroidism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated hypoparathyroidism due to agenesis of parathyroid gland

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hyperparathyroidism 4

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000272162 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05044955).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004752.4. 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
	GCM2	NM_004752.4	MANE Select	c.1462G>T	p.Ala488Ser	missense	Exon 5 of 5	NP_004743.1	O75603

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCM2	ENST00000379491.5	TSL:1 MANE Select	c.1462G>T	p.Ala488Ser	missense	Exon 5 of 5	ENSP00000368805.4	O75603
	ENSG00000272162	ENST00000480294.1	TSL:2	n.101-17459C>A		intron	N/A	ENSP00000417929.1	F8WBI7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000279 AC: 7 AN: 251324 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000326

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000150 AC: 22 AN: 1461868 Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.000554 AC: 22 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000341 Hom.: 0

ExAC AF: 0.0000494 AC: 6

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	7.3
DANN	Benign	0.94
DEOGEN2	Benign	0.073	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.050	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.30
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.064
Sift	Benign	0.077	T
Sift4G	Benign	0.16	T
Polyphen		0.33	B
Vest4		0.073
MutPred		0.24		Gain of disorder (P = 0.0184)
MVP		0.69
MPC		0.24
ClinPred		0.021	T
GERP RS		1.6
Varity_R		0.059
gMVP		0.13
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs751668850; hg19: chr6-10874287;