chr2-190880915-GCAGCAC-G

Variant names:

• chr2-190880915-GCAGCAC-G
• rs1293884901
• NM_014905.5:c.-168_-163delAGCACC

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_014905.5(GLS):​c.-168_-163delAGCACC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 916,828 control chromosomes in the GnomAD database, including 31 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0047 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (23 hom.)
• Consequence: GLS NM_014905.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.606
• 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: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00469 (693/147896) while in subpopulation AFR AF = 0.0134 (532/39576). AF 95% confidence interval is 0.0125. There are 8 homozygotes in GnomAd4. There are 337 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR,Unknown,AD gene

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.-168_-163delAGCACC		5_prime_UTR	Exon 1 of 18	NP_055720.3
	GLS	NM_001437282.1		c.-168_-163delAGCACC		5_prime_UTR	Exon 1 of 17	NP_001424211.1	H7C201
	GLS	NM_001256310.2		c.-168_-163delAGCACC		5_prime_UTR	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.-168_-163delAGCACC		5_prime_UTR	Exon 1 of 18	ENSP00000317379.3	O94925-1
	GLS	ENST00000338435.9	TSL:1	c.-168_-163delAGCACC		5_prime_UTR	Exon 1 of 15	ENSP00000340689.4	O94925-3
	GLS	ENST00000479552.1	TSL:1	n.46_51delAGCACC		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.00470 AC: 694 AN: 147778 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00529

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00588

Gnomad SAS AF: 0.00306

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000403

Gnomad OTH AF: 0.00595

GnomAD4 exome AF: 0.00114 AC: 878 AN: 768932 Hom.: 23 AF XY: 0.00108 AC XY: 430 AN XY: 397930

African (AFR) AF: 0.0124 AC: 218 AN: 17584

American (AMR) AF: 0.00383 AC: 109 AN: 28492

Ashkenazi Jewish (ASJ) AF: 0.0000541 AC: 1 AN: 18490

East Asian (EAS) AF: 0.00355 AC: 100 AN: 28180

South Asian (SAS) AF: 0.00147 AC: 93 AN: 63386

European-Finnish (FIN) AF: 0.000121 AC: 4 AN: 33114

Middle Eastern (MID) AF: 0.00391 AC: 11 AN: 2814

European-Non Finnish (NFE) AF: 0.000466 AC: 252 AN: 540576

Other (OTH) AF: 0.00248 AC: 90 AN: 36296

GnomAD4 genome AF: 0.00469 AC: 693 AN: 147896 Hom.: 8 Cov.: 32 AF XY: 0.00466 AC XY: 337 AN XY: 72270

African (AFR) AF: 0.0134 AC: 532 AN: 39576

American (AMR) AF: 0.00528 AC: 78 AN: 14762

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3398

East Asian (EAS) AF: 0.00590 AC: 29 AN: 4914

South Asian (SAS) AF: 0.00327 AC: 15 AN: 4582

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10492

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.000403 AC: 27 AN: 66946

Other (OTH) AF: 0.00589 AC: 12 AN: 2038

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.61
Mutation Taster		=298/2	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1293884901; hg19: chr2-191745641;