5-175684269-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001367711.1(HRH2):c.1036A>G(p.Ser346Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HRH2 NM_001367711.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.23

Genes affected

HRH2 (HGNC:5183): (histamine receptor H2) Histamine is a ubiquitous messenger molecule released from mast cells, enterochromaffin-like cells, and neurons. Its various actions are mediated by histamine receptors H1, H2, H3 and H4. Histamine receptor H2 belongs to the family 1 of G protein-coupled receptors. It is an integral membrane protein and stimulates gastric acid secretion. It also regulates gastrointestinal motility and intestinal secretion and is thought to be involved in regulating cell growth and differentiation. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, HRH2
• BP4: Computational evidence support a benign effect (MetaRNN=0.10929263).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HRH2	NM_001367711.1	c.1036A>G	p.Ser346Gly	missense_variant	2/3	ENST00000636584.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HRH2	ENST00000636584.2	c.1036A>G	p.Ser346Gly	missense_variant	2/3	3	NM_001367711.1	P1
HRH2	ENST00000377291.2	c.1036A>G	p.Ser346Gly	missense_variant	2/3	1
HRH2	ENST00000624694.2	c.1036A>G	p.Ser346Gly	missense_variant, NMD_transcript_variant	1/3	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

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

Jan 02, 2024

The c.1036A>G (p.S346G) alteration is located in exon 1 (coding exon 1) of the HRH2 gene. This alteration results from a A to G substitution at nucleotide position 1036, causing the serine (S) at amino acid position 346 to be replaced by a glycine (G). 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	0.061
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	19
Dann	Uncertain	1.0
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.65	T;T;T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.1	M;.;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.78	N;.;N
REVEL	Benign	0.091
Sift	Uncertain	0.012	D;.;D
Sift4G	Uncertain	0.028	D;.;D
Polyphen		0.0010	.;.;B
Vest4		0.043
MutPred		0.096		Loss of glycosylation at S346 (P = 0.0969);Loss of glycosylation at S346 (P = 0.0969);Loss of glycosylation at S346 (P = 0.0969);
MVP		0.63
MPC		0.89
ClinPred		0.38	T
GERP RS		2.4
Varity_R		0.18
gMVP		0.17

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: chr5-175111272;