chr10-87094318-C-G

Variant names:

• chr10-87094318-C-G
• rs797045598
• NM_005271.5:c.445+7G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005271.5(GLUD1):​c.445+7G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,451,416 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GLUD1 NM_005271.5 splice_region, intron
• Scores: Splicing: ADA: 0.00003646
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.214
• Publications: 0 publications found

Genes affected

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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLUD1	NM_005271.5	c.445+7G>C		splice_region_variant, intron_variant	Intron 1 of 12	ENST00000277865.5	NP_005262.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLUD1	ENST00000277865.5	c.445+7G>C		splice_region_variant, intron_variant	Intron 1 of 12	1	NM_005271.5	ENSP00000277865.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1451416 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 721476

African (AFR) AF: 0.00 AC: 0 AN: 33238

American (AMR) AF: 0.00 AC: 0 AN: 43320

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25928

East Asian (EAS) AF: 0.00 AC: 0 AN: 39282

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85274

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51978

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4464

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108088

Other (OTH) AF: 0.00 AC: 0 AN: 59844

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	9.4
DANN	Benign	0.84
PhyloP100		-0.21
PromoterAI		-0.017	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000036
dbscSNV1_RF	Benign	0.0
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: rs797045598; hg19: chr10-88854075;