17-63880878-T-C

Position:

• chr17-63880878-T-C

Variant summary

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

The NM_002059.5(GH2):​c.350A>G​(p.Gln117Arg) variant causes a missense change. 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_002059.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.87

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.350A>G	p.Gln117Arg	missense_variant	4/5	ENST00000423893.7	NP_002050.1
GH2	NM_022557.4	c.350A>G	p.Gln117Arg	missense_variant	4/4		NP_072051.1
GH2	NM_022558.4	c.350A>G	p.Gln117Arg	missense_variant	4/5		NP_072052.1
GH2	NM_022556.4	c.305A>G	p.Gln102Arg	missense_variant	4/5		NP_072050.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GH2	ENST00000423893.7	c.350A>G	p.Gln117Arg	missense_variant	4/5	1	NM_002059.5	ENSP00000409294.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251358 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135886

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000880

Gnomad OTH exome AF: 0.00

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

Dec 06, 2022

The c.350A>G (p.Q117R) alteration is located in exon 4 (coding exon 4) of the GH2 gene. This alteration results from a A to G substitution at nucleotide position 350, causing the glutamine (Q) at amino acid position 117 to be replaced by an arginine (R). 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	Uncertain	0.051	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	15
DANN	Benign	0.52
DEOGEN2	Benign	0.046	T;.;.;T;.
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.70	T;T;T;T;T
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.65	D;D;D;D;D
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	1.9	.;.;L;L;L
PrimateAI	Uncertain	0.48	T
PROVEAN	Uncertain	-2.5	.;D;N;N;N
REVEL	Uncertain	0.32
Sift	Benign	0.18	.;T;T;T;T
Sift4G	Benign	0.16	T;T;T;T;T
Polyphen		0.0	.;.;.;B;.
Vest4		0.68
MutPred		0.71		.;.;Gain of MoRF binding (P = 0.0629);Gain of MoRF binding (P = 0.0629);Gain of MoRF binding (P = 0.0629);
MVP		0.71
MPC		0.065
ClinPred		0.13	T
GERP RS		2.0
Varity_R		0.11
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1342142381; hg19: chr17-61958238;