17-63880839-C-T

Variant names:

• chr17-63880839-C-T
• rs1366247658
• NM_002059.5:c.389G>A

Variant summary

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

The NM_002059.5(GH2):​c.389G>A​(p.Gly130Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,810 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GH2 NM_002059.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.80

Genes affected

GH2 (HGNC:4262): (growth hormone 2) The protein encoded by this gene is a member of the somatotropin/prolactin family of hormones which play an important role in growth control. The gene, along with four other related genes, is located at the growth hormone locus on chromosome 17 where they are interspersed in the same transcriptional orientation; an arrangement which is thought to have evolved by a series of gene duplications. The five genes share a remarkably high degree of sequence identity. Alternative splicing generates additional isoforms of each of the five growth hormones, leading to further diversity and potential for specialization. As in the case of its pituitary counterpart, growth hormone 1, the predominant isoform of this particular family member shows similar somatogenic activity, with reduced lactogenic activity. Mutations in this gene lead to placental growth hormone/lactogen deficiency. [provided by RefSeq, Jul 2008]

ACMG classification

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
GH2	NM_002059.5	c.389G>A	p.Gly130Asp	missense_variant	Exon 4 of 5	ENST00000423893.7	NP_002050.1
GH2	NM_022557.4	c.389G>A	p.Gly130Asp	missense_variant	Exon 4 of 4		NP_072051.1
GH2	NM_022558.4	c.389G>A	p.Gly130Asp	missense_variant	Exon 4 of 5		NP_072052.1
GH2	NM_022556.4	c.344G>A	p.Gly115Asp	missense_variant	Exon 4 of 5		NP_072050.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GH2	ENST00000423893.7	c.389G>A	p.Gly130Asp	missense_variant	Exon 4 of 5	1	NM_002059.5	ENSP00000409294.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461810 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727208

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 10, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.389G>A (p.G130D) alteration is located in exon 4 (coding exon 4) of the GH2 gene. This alteration results from a G to A substitution at nucleotide position 389, causing the glycine (G) at amino acid position 130 to be replaced by an aspartic acid (D). 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	0.14
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.075	T;.;.;T;.
Eigen	Benign	0.13
Eigen_PC	Benign	-0.027
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.69	T;T;T;T;T
M_CAP	Benign	0.038	D
MetaRNN	Uncertain	0.69	D;D;D;D;D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Uncertain	2.3	.;.;M;M;M
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.0	.;D;N;D;N
REVEL	Uncertain	0.38
Sift	Benign	0.13	.;T;T;T;T
Sift4G	Benign	0.22	T;T;T;T;T
Polyphen		1.0	.;.;.;D;.
Vest4		0.87
MVP		0.86
MPC		0.082
ClinPred		0.88	D
GERP RS		3.1
Varity_R		0.15
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1366247658; hg19: chr17-61958199; COSMIC: COSV60426722;