chr1-37567000-C-T

Variant names:

• chr1-37567000-C-T
• rs758821126
• NM_013285.3:c.2051G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_013285.3(GNL2):​c.2051G>A​(p.Arg684Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000106 in 1,610,414 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: GNL2 NM_013285.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.96

Genes affected

GNL2 (HGNC:29925): (G protein nucleolar 2) Enables RNA binding activity. Predicted to be involved in ribosome biogenesis. Located in nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

DNALI1 (HGNC:14353): (dynein axonemal light intermediate chain 1) This gene is the human homolog of the Chlamydomonas inner dynein arm gene, p28. The precise function of this gene is not known, however, it is a potential candidate for immotile cilia syndrome (ICS). Ultrastructural defects of the inner dynein arms are seen in patients with ICS. Immotile mutant strains of Chlamydomonas, a biflagellated algae, exhibit similar defects. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28959107).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNL2	NM_013285.3	c.2051G>A	p.Arg684Gln	missense_variant	Exon 16 of 16	ENST00000373062.8	NP_037417.1
DNALI1	NM_003462.5	c.*1939C>T		downstream_gene_variant		ENST00000652629.1	NP_003453.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNL2	ENST00000373062.8	c.2051G>A	p.Arg684Gln	missense_variant	Exon 16 of 16	1	NM_013285.3	ENSP00000362153.3
DNALI1	ENST00000652629.1	c.*1939C>T		downstream_gene_variant			NM_003462.5	ENSP00000498620.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 151892 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000121 AC: 3 AN: 247882 Hom.: 0 AF XY: 0.0000150 AC XY: 2 AN XY: 133672

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000891 AC: 13 AN: 1458522 Hom.: 0 Cov.: 31 AF XY: 0.00000827 AC XY: 6 AN XY: 725172

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000227

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 151892 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74156

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000982

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2051G>A (p.R684Q) alteration is located in exon 16 (coding exon 16) of the GNL2 gene. This alteration results from a G to A substitution at nucleotide position 2051, causing the arginine (R) at amino acid position 684 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.37
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.060	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.099
Sift	Benign	0.19	T
Sift4G	Benign	0.33	T
Polyphen		1.0	D
Vest4		0.37
MutPred		0.24		Gain of helix (P = 0.132);
MVP		0.31
MPC		0.50
ClinPred		0.92	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.19

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

Publications

LitVar

Other links and lift over

dbSNP: rs758821126; hg19: chr1-38032601;