chr2-190880915-G-GCAGCAC

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_014905.5(GLS):​c.-168_-163dupAGCACC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000622 in 916,810 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000072 (1 hom.)
• Consequence: GLS NM_014905.5 5_prime_UTR
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.00
• 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: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 2-190880915-G-GCAGCAC is Benign according to our data. Variant chr2-190880915-G-GCAGCAC is described in ClinVar as Likely_benign. ClinVar VariationId is 3358130.Status of the report is no_assertion_criteria_provided, 0 stars.

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_-163dupAGCACC		5_prime_UTR	Exon 1 of 18	NP_055720.3
	GLS	NM_001437282.1		c.-168_-163dupAGCACC		5_prime_UTR	Exon 1 of 17	NP_001424211.1	H7C201
	GLS	NM_001256310.2		c.-168_-163dupAGCACC		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_-163dupAGCACC		5_prime_UTR	Exon 1 of 18	ENSP00000317379.3	O94925-1
	GLS	ENST00000338435.9	TSL:1	c.-168_-163dupAGCACC		5_prime_UTR	Exon 1 of 15	ENSP00000340689.4	O94925-3
	GLS	ENST00000479552.1	TSL:1	n.46_51dupAGCACC		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.0000135 AC: 2 AN: 147782 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000203

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000149

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000715 AC: 55 AN: 769028 Hom.: 1 Cov.: 12 AF XY: 0.0000729 AC XY: 29 AN XY: 397992

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000568 AC: 1 AN: 17608

American (AMR) AF: 0.00 AC: 0 AN: 28516

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18490

East Asian (EAS) AF: 0.00 AC: 0 AN: 28198

South Asian (SAS) AF: 0.00 AC: 0 AN: 63434

European-Finnish (FIN) AF: 0.000151 AC: 5 AN: 33094

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2814

European-Non Finnish (NFE) AF: 0.0000888 AC: 48 AN: 540568

Other (OTH) AF: 0.0000275 AC: 1 AN: 36306

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000135 AC: 2 AN: 147782 Hom.: 0 Cov.: 32 AF XY: 0.0000277 AC XY: 2 AN XY: 72148

African (AFR) AF: 0.00 AC: 0 AN: 39462

American (AMR) AF: 0.00 AC: 0 AN: 14740

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

East Asian (EAS) AF: 0.000203 AC: 1 AN: 4930

South Asian (SAS) AF: 0.00 AC: 0 AN: 4580

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.0000149 AC: 1 AN: 66952

Other (OTH) AF: 0.00 AC: 0 AN: 2018

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	GLS-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0

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;