chr6-10877343-C-G

Variant names:

• chr6-10877343-C-G
• rs104893959
• NM_004752.4:c.140G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_004752.4(GCM2):​c.140G>C​(p.Arg47Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R47H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GCM2 NM_004752.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.75
• Publications: 0 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_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-10877344-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1707105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCM2	NM_004752.4	c.140G>C	p.Arg47Pro	missense_variant	Exon 2 of 5	ENST00000379491.5	NP_004743.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCM2	ENST00000379491.5	c.140G>C	p.Arg47Pro	missense_variant	Exon 2 of 5	1	NM_004752.4	ENSP00000368805.4
ENSG00000272162	ENST00000480294.1	n.101-14170C>G		intron_variant	Intron 3 of 18	2		ENSP00000417929.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.087	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		3.8
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.84		Loss of MoRF binding (P = 0.0517);
MVP		0.93
MPC		0.95
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.92
gMVP		0.94
Mutation Taster		=15/85	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs104893959; hg19: chr6-10877576;