chr10-87094394-C-T

Variant names:

• chr10-87094394-C-T
• rs139579928
• NM_005271.5:c.376G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0077 (13 hom., cov: 31)
  • Exomes 𝑓: 0.00089 (14 hom.)
• Consequence: GLUD1 NM_005271.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.71
• Publications: 1 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: 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 ClinVar as Benign/Likely_benign. ClinVar VariationId 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.
• BS2: High Homozygotes in GnomAd4 at 13 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005271.5. 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
	GLUD1	NM_005271.5	MANE Select	c.376G>A	p.Asp126Asn	missense	Exon 1 of 13	NP_005262.1
	GLUD1	NM_001318904.2		c.-353G>A		5_prime_UTR	Exon 1 of 14	NP_001305833.1
	GLUD1	NM_001318905.2		c.-479G>A		5_prime_UTR	Exon 1 of 16	NP_001305834.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLUD1	ENST00000277865.5	TSL:1 MANE Select	c.376G>A	p.Asp126Asn	missense	Exon 1 of 13	ENSP00000277865.4
	SHLD2	ENST00000943977.1		c.-400C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 10	ENSP00000614036.1
	SHLD2	ENST00000898041.1		c.-400C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	ENSP00000568100.1

Frequencies

GnomAD3 genomes AF: 0.00764 AC: 1162 AN: 152134 Hom.: 13 Cov.: 31

Gnomad AFR AF: 0.0274

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00209 AC: 522 AN: 249766 AF XY: 0.00159

Gnomad AFR exome AF: 0.0286

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000622

Gnomad OTH exome AF: 0.000985

GnomAD4 exome AF: 0.000892 AC: 1304 AN: 1461078 Hom.: 14 Cov.: 32 AF XY: 0.000791 AC XY: 575 AN XY: 726854

African (AFR) AF: 0.0324 AC: 1084 AN: 33460

American (AMR) AF: 0.00136 AC: 61 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53236

Middle Eastern (MID) AF: 0.00129 AC: 7 AN: 5436

European-Non Finnish (NFE) AF: 0.0000225 AC: 25 AN: 1111884

Other (OTH) AF: 0.00194 AC: 117 AN: 60338

GnomAD4 genome AF: 0.00765 AC: 1165 AN: 152248 Hom.: 13 Cov.: 31 AF XY: 0.00739 AC XY: 550 AN XY: 74432

African (AFR) AF: 0.0275 AC: 1141 AN: 41550

American (AMR) AF: 0.000849 AC: 13 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67990

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00282 Hom.: 1

Bravo AF: 0.00890

ESP6500AA AF: 0.0238 AC: 105

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00242 AC: 294

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hyperinsulinism-hyperammonemia syndrome (2)
-	-	2	not provided (2)
-	-	1	Monogenic diabetes (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.41	N
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	0.23	N
PhyloP100		3.7
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.83	N
REVEL	Uncertain	0.32
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0020	B
Vest4		0.086
MVP		0.92
MPC		1.1
ClinPred		0.014	T
GERP RS		2.3
PromoterAI		-0.0096	Neutral
Varity_R		0.30
gMVP		0.59
Mutation Taster		=87/13	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: rs139579928; hg19: chr10-88854151; COSMIC: COSV107204410; COSMIC: COSV107204410;