6-10874047-C-A

Position:

• chr6-10874047-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004752.4(GCM2):​c.1469G>T​(p.Ser490Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GCM2 NM_004752.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0420

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]

ENSG00000272162 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27864397).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GCM2	NM_004752.4	c.1469G>T	p.Ser490Ile	missense_variant	5/5	ENST00000379491.5	NP_004743.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCM2	ENST00000379491.5	c.1469G>T	p.Ser490Ile	missense_variant	5/5	1	NM_004752.4	ENSP00000368805.4
ENSG00000272162	ENST00000480294.1	n.101-17466C>A		intron_variant		2		ENSP00000417929.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hyperparathyroidism 4;C5394383:Hypoparathyroidism, familial isolated, 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 12, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.083
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.012	D
Polyphen		0.58	P
Vest4		0.20
MutPred		0.36		Loss of disorder (P = 0.0149);
MVP		0.78
MPC		0.54
ClinPred		0.89	D
GERP RS		-0.32
Varity_R		0.12
gMVP		0.51

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

LitVar

Other links and lift over

dbSNP: rs959455592; hg19: chr6-10874280;