2-190881150-C-T

Variant names:

• chr2-190881150-C-T
• rs1307572661
• NM_014905.5:c.66C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BS1

The NM_014905.5(GLS):​c.66C>T​(p.Ser22Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000214 in 1,402,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GLS NM_014905.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.709
• Publications: 1 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: Ambry Genetics, ClinGen
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.00000214 (3/1402010) while in subpopulation EAS AF = 0.0000556 (2/35964). AF 95% confidence interval is 0.00000921. There are 0 homozygotes in GnomAdExome4. There are 1 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

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.66C>T	p.Ser22Ser	synonymous	Exon 1 of 18	NP_055720.3
	GLS	NM_001437282.1		c.66C>T	p.Ser22Ser	synonymous	Exon 1 of 17	NP_001424211.1	H7C201
	GLS	NM_001256310.2		c.66C>T	p.Ser22Ser	synonymous	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.66C>T	p.Ser22Ser	synonymous	Exon 1 of 18	ENSP00000317379.3	O94925-1
	GLS	ENST00000338435.9	TSL:1	c.66C>T	p.Ser22Ser	synonymous	Exon 1 of 15	ENSP00000340689.4	O94925-3
	GLS	ENST00000479552.1	TSL:1	n.279C>T		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000214 AC: 3 AN: 1402010 Hom.: 0 Cov.: 32 AF XY: 0.00000144 AC XY: 1 AN XY: 694680

African (AFR) AF: 0.00 AC: 0 AN: 31624

American (AMR) AF: 0.00 AC: 0 AN: 38778

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24870

East Asian (EAS) AF: 0.0000556 AC: 2 AN: 35964

South Asian (SAS) AF: 0.00 AC: 0 AN: 80936

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37052

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4108

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1090410

Other (OTH) AF: 0.0000172 AC: 1 AN: 58268

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.00174 AC: 6 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	15
DANN	Benign	0.91
PhyloP100		-0.71
PromoterAI		0.17	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.33		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.33		Position offset: -6

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

Other links and lift over

dbSNP: rs1307572661; hg19: chr2-191745876;