chr2-190964686-C-G

Variant names:

• chr2-190964686-C-G
• rs3088307
• NM_014905.5:c.*1700C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014905.5(GLS):​c.*1700C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.383 in 152,002 control chromosomes in the GnomAD database, including 12,172 homozygotes. 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: 𝑓 0.38 (12167 hom., cov: 32)
  • Exomes 𝑓: 0.69 (5 hom.)
• Consequence: GLS NM_014905.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.291
• Publications: 18 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]

STAT1 (HGNC:11362): (signal transducer and activator of transcription 1) The protein encoded by this gene is a member of the STAT protein family. In response to cytokines and growth factors, STAT family members are phosphorylated by the receptor associated kinases, and then form homo- or heterodimers that translocate to the cell nucleus where they act as transcription activators. The protein encoded by this gene can be activated by various ligands including interferon-alpha, interferon-gamma, EGF, PDGF and IL6. This protein mediates the expression of a variety of genes, which is thought to be important for cell viability in response to different cell stimuli and pathogens. The protein plays an important role in immune responses to viral, fungal and mycobacterial pathogens. Mutations in this gene are associated with Immunodeficiency 31B, 31A, and 31C. [provided by RefSeq, Jun 2020]

STAT1 Gene-Disease associations (from GenCC):

• autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Illumina, ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, Ambry Genetics
• immunodeficiency 31B

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, Orphanet, G2P, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.463 is higher than 0.05.

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.*1700C>G		3_prime_UTR	Exon 18 of 18	NP_055720.3
	GLS	NM_001437282.1		c.*1660C>G		3_prime_UTR	Exon 17 of 17	NP_001424211.1	H7C201

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLS	ENST00000320717.8	TSL:1 MANE Select	c.*1700C>G		3_prime_UTR	Exon 18 of 18	ENSP00000317379.3	O94925-1
	GLS	ENST00000950145.1		c.*1700C>G		3_prime_UTR	Exon 19 of 19	ENSP00000620204.1
	GLS	ENST00000950146.1		c.*1700C>G		3_prime_UTR	Exon 16 of 16	ENSP00000620205.1

Frequencies

GnomAD3 genomes AF: 0.383 AC: 58226 AN: 151868 Hom.: 12167 Cov.: 32

Gnomad AFR AF: 0.279

Gnomad AMI AF: 0.392

Gnomad AMR AF: 0.295

Gnomad ASJ AF: 0.340

Gnomad EAS AF: 0.103

Gnomad SAS AF: 0.342

Gnomad FIN AF: 0.554

Gnomad MID AF: 0.280

Gnomad NFE AF: 0.468

Gnomad OTH AF: 0.365

GnomAD4 exome AF: 0.688 AC: 11 AN: 16 Hom.: 5 Cov.: 0 AF XY: 0.714 AC XY: 10 AN XY: 14

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.700 AC: 7 AN: 10

Other (OTH) AF: 1.00 AC: 4 AN: 4

GnomAD4 genome AF: 0.383 AC: 58239 AN: 151986 Hom.: 12167 Cov.: 32 AF XY: 0.386 AC XY: 28635 AN XY: 74268

African (AFR) AF: 0.279 AC: 11559 AN: 41464

American (AMR) AF: 0.295 AC: 4488 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.340 AC: 1180 AN: 3470

East Asian (EAS) AF: 0.102 AC: 530 AN: 5178

South Asian (SAS) AF: 0.342 AC: 1649 AN: 4816

European-Finnish (FIN) AF: 0.554 AC: 5852 AN: 10556

Middle Eastern (MID) AF: 0.271 AC: 79 AN: 292

European-Non Finnish (NFE) AF: 0.468 AC: 31779 AN: 67972

Other (OTH) AF: 0.364 AC: 767 AN: 2110

Alfa AF: 0.435 Hom.: 2035

Bravo AF: 0.356

Asia WGS AF: 0.240 AC: 835 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.6
DANN	Benign	0.57
PhyloP100		0.29
Mutation Taster		=100/0	polymorphism (auto)

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: rs3088307; hg19: chr2-191829412;