chr2-190881163-C-G

Variant names:

• chr2-190881163-C-G
• NM_014905.5:c.79C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014905.5(GLS):​c.79C>G​(p.Arg27Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GLS NM_014905.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.387
• Publications: 0 publications found

Genes affected

GLS (HGNC:4331): (glutaminase) This gene encodes the K-type mitochondrial glutaminase. The encoded protein is an phosphate-activated amidohydrolase that catalyzes the hydrolysis of glutamine to glutamate and ammonia. This protein is primarily expressed in the brain and kidney plays an essential role in generating energy for metabolism, synthesizing the brain neurotransmitter glutamate and maintaining acid-base balance in the kidney. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jan 2012]

GLS Gene-Disease associations (from GenCC):

• glutaminase deficiency

  Inheritance: AR Classification: DEFINITIVE, MODERATE Submitted by: ClinGen, Ambry Genetics
• global developmental delay, progressive ataxia, and elevated glutamine

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development

  Inheritance: AD, Unknown Classification: MODERATE, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• developmental and epileptic encephalopathy, 71

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000228509 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24520457).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014905.5. 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
	GLS	NM_014905.5	MANE Select	c.79C>G	p.Arg27Gly	missense	Exon 1 of 18	NP_055720.3
	GLS	NM_001437282.1		c.79C>G	p.Arg27Gly	missense	Exon 1 of 17	NP_001424211.1	H7C201
	GLS	NM_001256310.2		c.79C>G	p.Arg27Gly	missense	Exon 1 of 15	NP_001243239.1	O94925-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLS	ENST00000320717.8	TSL:1 MANE Select	c.79C>G	p.Arg27Gly	missense	Exon 1 of 18	ENSP00000317379.3	O94925-1
	GLS	ENST00000338435.9	TSL:1	c.79C>G	p.Arg27Gly	missense	Exon 1 of 15	ENSP00000340689.4	O94925-3
	GLS	ENST00000479552.1	TSL:1	n.292C>G		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.042	T
Eigen	Benign	-0.051
Eigen_PC	Benign	-0.072
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.54	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.39
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.60	N
REVEL	Benign	0.087
Sift	Uncertain	0.025	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.56	P
Vest4		0.47
MutPred		0.29		Loss of helix (P = 0.0068)
MVP		0.69
MPC		1.2
ClinPred		0.79	D
GERP RS		2.2
PromoterAI		-0.0057	Neutral
Varity_R		0.10
gMVP		0.40
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

hg19: chr2-191745889;