Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_005271.5(GLUD1):c.376G>A(p.Asp126Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00153 in 1,613,326 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
GLUD1 (HGNC:4335): (glutamate dehydrogenase 1) This gene encodes glutamate dehydrogenase, which is a mitochondrial matrix enzyme that catalyzes the oxidative deamination of glutamate to alpha-ketoglutarate and ammonia. This enzyme has an important role in regulating amino acid-induced insulin secretion. It is allosterically activated by ADP and inhibited by GTP and ATP. Activating mutations in this gene are a common cause of congenital hyperinsulinism. Alternative splicing of this gene results in multiple transcript variants. The related glutamate dehydrogenase 2 gene on the human X-chromosome originated from this gene via retrotransposition and encodes a soluble form of glutamate dehydrogenase. Related pseudogenes have been identified on chromosomes 10, 18 and X. [provided by RefSeq, Jan 2016]
SHLD2 (HGNC:28773): (shieldin complex subunit 2) Involved in negative regulation of double-strand break repair via homologous recombination; positive regulation of double-strand break repair via nonhomologous end joining; and positive regulation of isotype switching. Located in nucleus and site of double-strand break. [provided by Alliance of Genome Resources, Apr 2022]
Our verdict: Benign. The variant received -20 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.011810064).
BP6
Variant 10-87094394-C-T is Benign according to our data. Variant chr10-87094394-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 259740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87094394-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 259740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87094394-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 259740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87094394-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 259740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87094394-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 259740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87094394-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 259740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87094394-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 259740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87094394-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 259740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87094394-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 259740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87094394-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 259740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87094394-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 259740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87094394-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 259740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87094394-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 259740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87094394-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 259740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87094394-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 259740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87094394-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 259740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87094394-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 259740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87094394-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 259740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87094394-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 259740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87094394-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 259740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87094394-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 259740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87094394-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 259740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87094394-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 259740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87094394-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 259740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87094394-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 259740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87094394-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 259740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87094394-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 259740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87094394-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 259740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87094394-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 259740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87094394-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 259740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87094394-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 259740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87094394-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 259740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87094394-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 259740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87094394-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 259740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87094394-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 259740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00765 (1165/152248) while in subpopulation AFR AF = 0.0275 (1141/41550). AF 95% confidence interval is 0.0261. There are 13 homozygotes in GnomAd4. There are 550 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
not providedBenign:2
Mar 03, 2015
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing
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Breakthrough Genomics, Breakthrough Genomics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:not provided
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not specifiedBenign:1
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PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing
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Monogenic diabetesBenign:1
Dec 21, 2018
Personalized Diabetes Medicine Program, University of Maryland School of Medicine
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:research
ACMG criteria: BP5 (seen in patient with GCK pathogenic variant), BS2 (found in 74 controls in T2DM database and 58 cases) and BA1 (2.8% MAF in gnomAD AA and 9 Today study individuals has the same variant ): benign; NOTE: GLUD1 variants for hyperinsulinemia are found in exons 6, 7, 10, 11 and 12, this variant is in exon 1." (REVEL 0.318 + PP3/4 predictors + BP4/6 predictor: conflicting evidence, not using) -