17-76074893-T-C

Variant names:

• chr17-76074893-T-C
• rs770058014
• NM_003857.4:c.10T>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003857.4(GALR2):​c.10T>C​(p.Ser4Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,375,392 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: GALR2 NM_003857.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.252

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1440815).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALR2	NM_003857.4	c.10T>C	p.Ser4Pro	missense_variant	Exon 1 of 2	ENST00000329003.4	NP_003848.1
GALR2	XM_011525427.4	c.76-237T>C		intron_variant	Intron 2 of 3		XP_011523729.1
GALR2	XM_047436984.1	c.76-237T>C		intron_variant	Intron 2 of 3		XP_047292940.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALR2	ENST00000329003.4	c.10T>C	p.Ser4Pro	missense_variant	Exon 1 of 2	1	NM_003857.4	ENSP00000329684.3
ZACN	ENST00000591500.1	n.216+2717T>C		intron_variant	Intron 1 of 1	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000993 AC: 13 AN: 130872 Hom.: 0 AF XY: 0.0000989 AC XY: 7 AN XY: 70776

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00120

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 15 AN: 1375392 Hom.: 0 Cov.: 32 AF XY: 0.0000148 AC XY: 10 AN XY: 677886

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000336

Gnomad4 SAS exome AF: 0.0000258

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000174

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000189

ExAC AF: 0.0000196 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 15, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.10T>C (p.S4P) alteration is located in exon 1 (coding exon 1) of the GALR2 gene. This alteration results from a T to C substitution at nucleotide position 10, causing the serine (S) at amino acid position 4 to be replaced by a proline (P). 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	0.076
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.099	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.39	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.2	M
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.20
Sift	Uncertain	0.0080	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.91	P
Vest4		0.14
MutPred		0.32		Loss of glycosylation at S4 (P = 0.0151);
MVP		0.87
ClinPred		0.16	T
GERP RS		4.0
Varity_R		0.31
gMVP		0.72

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: rs770058014; hg19: chr17-74070974;