10-123666762-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_153442.4(GPR26):c.355C>G(p.Arg119Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,448,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GPR26 NM_153442.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.89

Genes affected

GPR26 (HGNC:4481): (G protein-coupled receptor 26) This gene encodes a G protein-couple receptor protein. G-protein-coupled receptors are a large family of membrane proteins that are involved in cellular responses to environmental stimuli, neurotransmitters, and hormones. The encoded protein may play a role in neurodegenerative diseases. Epigenetic silencing of this gene has been observed in gliomas. [provided by RefSeq, Sep 2016]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPR26	NM_153442.4	c.355C>G	p.Arg119Gly	missense_variant	1/3	ENST00000284674.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPR26	ENST00000284674.2	c.355C>G	p.Arg119Gly	missense_variant	1/3	1	NM_153442.4	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1448762 Hom.: 0 Cov.: 30 AF XY: 0.00000278 AC XY: 2 AN XY: 720590

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 12, 2024

The c.355C>G (p.R119G) alteration is located in exon 1 (coding exon 1) of the GPR26 gene. This alteration results from a C to G substitution at nucleotide position 355, causing the arginine (R) at amino acid position 119 to be replaced by a glycine (G). 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	0.22
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.090
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.024	T
MetaRNN	Pathogenic	0.95	D
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.35
Sift	Uncertain	0.029	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.97	D
Vest4		0.90
MutPred		0.83		Loss of MoRF binding (P = 0.0183);
MVP		0.83
MPC		2.3
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.55
gMVP		0.95

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-125426278;