2-132645512-C-G

Position:

• chr2-132645512-C-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001508.3(GPR39):​c.1268C>G​(p.Ser423Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00229 in 1,612,956 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (9 hom.)
• Consequence: GPR39 NM_001508.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.748

Genes affected

GPR39 (HGNC:4496): (G protein-coupled receptor 39) This gene is a member of the ghrelin receptor family and encodes a rhodopsin-type G-protein-coupled receptor (GPCR). The encoded protein is involved in zinc-dependent signaling in epithelial tissue in intestines, prostate and salivary glands. The protein may also be involved in the pathophysiology of depression. [provided by RefSeq, Jun 2016]

LYPD1 (HGNC:28431): (LY6/PLAUR domain containing 1) Predicted to enable acetylcholine receptor binding activity and acetylcholine receptor inhibitor activity. Predicted to be involved in acetylcholine receptor signaling pathway. Predicted to act upstream of or within several processes, including behavioral fear response; cholinergic synaptic transmission; and negative regulation of protein localization to plasma membrane. Predicted to be located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

GPR39 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008588046).
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPR39	NM_001508.3	c.1268C>G	p.Ser423Cys	missense_variant	2/2	ENST00000329321.4	NP_001499.1
LYPD1	NM_144586.7	c.*533G>C		3_prime_UTR_variant	3/3	ENST00000397463.3	NP_653187.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPR39	ENST00000329321.4	c.1268C>G	p.Ser423Cys	missense_variant	2/2	1	NM_001508.3	ENSP00000327417.3
LYPD1	ENST00000397463	c.*533G>C		3_prime_UTR_variant	3/3	1	NM_144586.7	ENSP00000380605.2
GPR39	ENST00000470071.1	n.971C>G		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.00169 AC: 256 AN: 151918 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000558

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00303

Gnomad OTH AF: 0.000960

GnomAD3 exomes AF: 0.00137 AC: 340 AN: 248976 Hom.: 0 AF XY: 0.00148 AC XY: 200 AN XY: 134784

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00108

Gnomad FIN exome AF: 0.00148

Gnomad NFE exome AF: 0.00214

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00235 AC: 3431 AN: 1460920 Hom.: 9 Cov.: 32 AF XY: 0.00237 AC XY: 1719 AN XY: 726836

Gnomad4 AFR exome AF: 0.000455

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00107

Gnomad4 FIN exome AF: 0.00110

Gnomad4 NFE exome AF: 0.00280

Gnomad4 OTH exome AF: 0.00197

GnomAD4 genome AF: 0.00168 AC: 256 AN: 152036 Hom.: 0 Cov.: 33 AF XY: 0.00149 AC XY: 111 AN XY: 74352

Gnomad4 AFR AF: 0.000556

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.000847

Gnomad4 NFE AF: 0.00303

Gnomad4 OTH AF: 0.000950

Alfa AF: 0.00252 Hom.: 0

Bravo AF: 0.00139

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00267 AC: 23

ExAC AF: 0.00133 AC: 161

Asia WGS AF: 0.000289 AC: 2 AN: 3478

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

Aug 22, 2023

The c.1268C>G (p.S423C) alteration is located in exon 2 (coding exon 2) of the GPR39 gene. This alteration results from a C to G substitution at nucleotide position 1268, causing the serine (S) at amino acid position 423 to be replaced by a cysteine (C). 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	0.082
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	16
DANN	Benign	0.87
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.27	T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.0086	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.90	L
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.067
Sift	Benign	0.089	T
Sift4G	Benign	0.095	T
Polyphen		0.33	B
Vest4		0.14
MVP		0.68
MPC		0.39
ClinPred		0.0060	T
GERP RS		4.3
Varity_R		0.039
gMVP		0.32

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: rs61757692; hg19: chr2-133403085;