rs76143708

Variant names:

• chr6-10873361-G-A
• rs76143708
• NM_004752.4:c.*634C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004752.4(GCM2):​c.*634C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0155 in 154,532 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.016 (72 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (0 hom.)
• Consequence: GCM2 NM_004752.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.250
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 6-10873361-G-A is Benign according to our data. Variant chr6-10873361-G-A is described in ClinVar as Benign. ClinVar VariationId is 354998.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0512 is higher than 0.05.

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.*634C>T		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.*634C>T		3_prime_UTR	Exon 5 of 5	ENSP00000368805.4	O75603
	ENSG00000272162	ENST00000480294.1	TSL:2	n.101-18152G>A		intron	N/A	ENSP00000417929.1	F8WBI7

Frequencies

GnomAD3 genomes AF: 0.0157 AC: 2392 AN: 152124 Hom.: 72 Cov.: 33

Gnomad AFR AF: 0.0531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00955

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0148

GnomAD4 exome AF: 0.00131 AC: 3 AN: 2290 Hom.: 0 Cov.: 0 AF XY: 0.00168 AC XY: 2 AN XY: 1192

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 4

American (AMR) AF: 0.00647 AC: 3 AN: 464

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4

East Asian (EAS) AF: 0.00 AC: 0 AN: 38

South Asian (SAS) AF: 0.00 AC: 0 AN: 200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1514

Other (OTH) AF: 0.00 AC: 0 AN: 56

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0225104), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0157 AC: 2396 AN: 152242 Hom.: 72 Cov.: 33 AF XY: 0.0153 AC XY: 1137 AN XY: 74422

African (AFR) AF: 0.0530 AC: 2204 AN: 41550

American (AMR) AF: 0.00954 AC: 146 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68014

Other (OTH) AF: 0.0147 AC: 31 AN: 2112

Alfa AF: 0.00630 Hom.: 3

Bravo AF: 0.0181

Asia WGS AF: 0.00202 AC: 7 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.3
DANN	Benign	0.65
PhyloP100		-0.25
Mutation Taster		=100/0	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: rs76143708; hg19: chr6-10873594;