5-175683912-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_001367711.1(HRH2):c.679A>G(p.Ile227Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: HRH2 NM_001367711.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0710

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 Likely_benign. 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=0.03899774).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HRH2	NM_001367711.1	c.679A>G	p.Ile227Val	missense_variant	2/3	ENST00000636584.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HRH2	ENST00000636584.2	c.679A>G	p.Ile227Val	missense_variant	2/3	3	NM_001367711.1	P1
HRH2	ENST00000377291.2	c.679A>G	p.Ile227Val	missense_variant	2/3	1
HRH2	ENST00000624694.2	c.679A>G	p.Ile227Val	missense_variant, NMD_transcript_variant	1/3	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461894 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

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 27, 2023

The c.679A>G (p.I227V) 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 679, causing the isoleucine (I) at amino acid position 227 to be replaced by a valine (V). 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	0.062
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	0.085
Dann	Benign	0.45
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.70	T;T;T
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.039	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.88	N;.;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.020	N;.;N
REVEL	Benign	0.061
Sift	Benign	0.58	T;.;T
Sift4G	Benign	1.0	T;.;T
Polyphen		0.0	.;.;B
Vest4		0.018
MutPred		0.35		Gain of ubiquitination at K223 (P = 0.1008);Gain of ubiquitination at K223 (P = 0.1008);Gain of ubiquitination at K223 (P = 0.1008);
MVP		0.26
MPC		0.71
ClinPred		0.051	T
GERP RS		-1.9
Varity_R		0.015
gMVP		0.27

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

LitVar

Other links and lift over

dbSNP: rs1025003696; hg19: chr5-175110915;