17-76074890-G-C

Variant names:

• chr17-76074890-G-C
• rs199821083
• NM_003857.4:c.7G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003857.4(GALR2):​c.7G>C​(p.Val3Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000728 in 1,373,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V3I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: GALR2 NM_003857.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0340
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.043177366).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003857.4. 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
	GALR2	NM_003857.4	MANE Select	c.7G>C	p.Val3Leu	missense	Exon 1 of 2	NP_003848.1	O43603

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALR2	ENST00000329003.4	TSL:1 MANE Select	c.7G>C	p.Val3Leu	missense	Exon 1 of 2	ENSP00000329684.3	O43603
	ZACN	ENST00000591500.1	TSL:4	n.216+2714G>C		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.28e-7 AC: 1 AN: 1373214 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 676598

African (AFR) AF: 0.00 AC: 0 AN: 31370

American (AMR) AF: 0.00 AC: 0 AN: 35280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24192

East Asian (EAS) AF: 0.00 AC: 0 AN: 35646

South Asian (SAS) AF: 0.00 AC: 0 AN: 76944

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33870

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4022

European-Non Finnish (NFE) AF: 9.31e-7 AC: 1 AN: 1074566

Other (OTH) AF: 0.00 AC: 0 AN: 57324

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	8.8
DANN	Benign	0.78
DEOGEN2	Benign	0.048	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N
PhyloP100		0.034
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.043
Sift	Benign	0.70	T
Sift4G	Benign	0.19	T
Polyphen		0.049	B
Vest4		0.069
MutPred		0.13		Loss of catalytic residue at V3 (P = 0.1397)
MVP		0.52
ClinPred		0.033	T
GERP RS		2.0
PromoterAI		0.011	Neutral
Varity_R		0.053
gMVP		0.30

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: rs199821083; hg19: chr17-74070971;