chr17-63880512-C-T

Position:

• chr17-63880512-C-T

Variant summary

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

The NM_022558.4(GH2):​c.459G>A​(p.Trp153*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GH2 NM_022558.4 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.75

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/exons	MANE	Protein	UniProt
GH2	NM_002059.5	c.463G>A	p.Glu155Lys	missense_variant	5/5	ENST00000423893.7	NP_002050.1
GH2	NM_022558.4	c.459G>A	p.Trp153*	stop_gained	5/5		NP_072052.1
GH2	NM_022557.4	c.716G>A	p.Gly239Glu	missense_variant	4/4		NP_072051.1
GH2	NM_022556.4	c.418G>A	p.Glu140Lys	missense_variant	5/5		NP_072050.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GH2	ENST00000423893.7	c.463G>A	p.Glu155Lys	missense_variant	5/5	1	NM_002059.5	ENSP00000409294.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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

Nov 21, 2023

The c.716G>A (p.G239E) 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 716, causing the glycine (G) at amino acid position 239 to be replaced by a glutamic acid (E). 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	0.16
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.059	T;.;T
Eigen	Benign	0.024
Eigen_PC	Benign	0.010
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.86	D;D;D
MetaRNN	Uncertain	0.73	D;D;D
MetaSVM	Benign	-0.95	T
PROVEAN	Uncertain	-2.9	.;D;D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0030	.;D;D
Sift4G	Uncertain	0.040	D;D;D
Polyphen		0.65	.;.;P
Vest4		0.58
MutPred		0.63		.;.;Gain of MoRF binding (P = 0.0174);
MVP		0.79
ClinPred		0.91	D
GERP RS		2.7
Varity_R		0.49

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-61957872; COSMIC: COSV60427829;