chr6-10873268-G-GA

Variant names:

• chr6-10873268-G-GA
• rs567863142
• NM_004752.4:c.*726dupT

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_004752.4(GCM2):​c.*726dupT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0032 in 151,540 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0032 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GCM2 NM_004752.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.419
• 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_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0032 (485/151540) while in subpopulation SAS AF = 0.00647 (31/4788). AF 95% confidence interval is 0.00484. There are 3 homozygotes in GnomAd4. There are 243 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 3 Unknown,AD,AR gene

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.*726dupT		3_prime_UTR	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.*726dupT		3_prime_UTR	Exon 5 of 5	ENSP00000368805.4	O75603
	ENSG00000272162	ENST00000480294.1	TSL:2	n.101-18237dupA		intron	N/A	ENSP00000417929.1	F8WBI7

Frequencies

GnomAD3 genomes AF: 0.00320 AC: 485 AN: 151422 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000631

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00158

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00668

Gnomad FIN AF: 0.00231

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00529

Gnomad OTH AF: 0.00337

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 18 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 10

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 14

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.00320 AC: 485 AN: 151540 Hom.: 3 Cov.: 33 AF XY: 0.00328 AC XY: 243 AN XY: 74028

African (AFR) AF: 0.000629 AC: 26 AN: 41350

American (AMR) AF: 0.00164 AC: 25 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00647 AC: 31 AN: 4788

European-Finnish (FIN) AF: 0.00231 AC: 24 AN: 10392

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00529 AC: 359 AN: 67832

Other (OTH) AF: 0.00333 AC: 7 AN: 2102

Alfa AF: 0.000868 Hom.: 0

Bravo AF: 0.00289

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Familial hypoparathyroidism (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.42
Mutation Taster		=100/0	polymorphism

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: rs567863142; hg19: chr6-10873501;