NM_003857.4:c.108C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003857.4(GALR2):​c.108C>G​(p.Phe36Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

GALR2
NM_003857.4 missense

Scores

4
8
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.84
Variant links:
Genes affected
GALR2 (HGNC:4133): (galanin receptor 2) Galanin is an important neuromodulator present in the brain, gastrointestinal system, and hypothalamopituitary axis. It is a 30-amino acid non-C-terminally amidated peptide that potently stimulates growth hormone secretion, inhibits cardiac vagal slowing of heart rate, abolishes sinus arrhythmia, and inhibits postprandial gastrointestinal motility. The actions of galanin are mediated through interaction with specific membrane receptors that are members of the 7-transmembrane family of G protein-coupled receptors. GALR2 interacts with the N-terminal residues of the galanin peptide. The primary signaling mechanism for GALR2 is through the phospholipase C/protein kinase C pathway (via Gq), in contrast to GALR1, which communicates its intracellular signal by inhibition of adenylyl cyclase through Gi. However, it has been demonstrated that GALR2 couples efficiently to both the Gq and Gi proteins to simultaneously activate 2 independent signal transduction pathways. [provided by RefSeq, Jul 2008]
ZACN (HGNC:29504): (zinc activated ion channel) LGICZ1 is a zinc-activated ligand-gated ion channel that defines a new subgroup of the cysteine-loop superfamily of ligand-gated ion channels (Davies et al., 2003 [PubMed 12381728]).[supplied by OMIM, Mar 2008]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GALR2NM_003857.4 linkc.108C>G p.Phe36Leu missense_variant Exon 1 of 2 ENST00000329003.4 NP_003848.1 O43603
GALR2XM_011525427.4 linkc.76-139C>G intron_variant Intron 2 of 3 XP_011523729.1
GALR2XM_047436984.1 linkc.76-139C>G intron_variant Intron 2 of 3 XP_047292940.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GALR2ENST00000329003.4 linkc.108C>G p.Phe36Leu missense_variant Exon 1 of 2 1 NM_003857.4 ENSP00000329684.3 O43603
ZACNENST00000591500.1 linkn.216+2815C>G intron_variant Intron 1 of 1 4

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

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.108C>G (p.F36L) alteration is located in exon 1 (coding exon 1) of the GALR2 gene. This alteration results from a C to G substitution at nucleotide position 108, causing the phenylalanine (F) at amino acid position 36 to be replaced by a leucine (L). 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
Pathogenic
0.87
BayesDel_addAF
Benign
-0.041
T
BayesDel_noAF
Benign
-0.30
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.28
T
Eigen
Uncertain
0.22
Eigen_PC
Benign
0.20
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.92
D
M_CAP
Benign
0.021
T
MetaRNN
Uncertain
0.61
D
MetaSVM
Benign
-0.90
T
MutationAssessor
Uncertain
2.1
M
PrimateAI
Pathogenic
0.84
D
PROVEAN
Pathogenic
-4.9
D
REVEL
Uncertain
0.30
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.010
D
Polyphen
1.0
D
Vest4
0.51
MutPred
0.68
Loss of catalytic residue at F36 (P = 0.1031);
MVP
0.70
ClinPred
1.0
D
GERP RS
3.8
Varity_R
0.92
gMVP
0.66

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: chr17-74071072; API