17-63880636-C-T

Variant names:

• chr17-63880636-C-T
• rs763776483
• ENST00000332800.7:c.592G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_022557.4(GH2):​c.592G>A​(p.Val198Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: GH2 NM_022557.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.881

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.049360335).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GH2	NM_002059.5	c.457-118G>A		intron_variant	Intron 4 of 4	ENST00000423893.7	NP_002050.1
GH2	NM_022557.4	c.592G>A	p.Val198Met	missense_variant	Exon 4 of 4		NP_072051.1
GH2	NM_022558.4	c.453-118G>A		intron_variant	Intron 4 of 4		NP_072052.1
GH2	NM_022556.4	c.412-118G>A		intron_variant	Intron 4 of 4		NP_072050.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GH2	ENST00000423893.7	c.457-118G>A		intron_variant	Intron 4 of 4	1	NM_002059.5	ENSP00000409294.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251462 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135910

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461780 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727196

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 01, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.592G>A (p.V198M) 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 592, causing the valine (V) at amino acid position 198 to be replaced by a methionine (M). 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
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.13
DANN	Benign	0.83
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0032	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-0.74	T
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.46	N
REVEL	Benign	0.17
Sift	Benign	0.12	T
Sift4G	Benign	0.14	T
Vest4		0.042
MutPred		0.17		Loss of catalytic residue at V198 (P = 0.0544);
MVP		0.040
MPC		0.078
ClinPred		0.033	T
GERP RS		-5.5
gMVP		0.12

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: rs763776483; hg19: chr17-61957996;