5-175684227-C-G

Position:

• chr5-175684227-C-G

Variant summary

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

The NM_001367711.1(HRH2):​c.994C>G​(p.Pro332Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,888 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HRH2 NM_001367711.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.248

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]

HRH2 (HGNC:):

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=0.03648424).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HRH2	NM_001367711.1	c.994C>G	p.Pro332Ala	missense_variant	2/3	ENST00000636584.2	NP_001354640.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HRH2	ENST00000636584.2	c.994C>G	p.Pro332Ala	missense_variant	2/3	3	NM_001367711.1	ENSP00000489742.1
HRH2	ENST00000377291.2	c.994C>G	p.Pro332Ala	missense_variant	2/3	1		ENSP00000366506.2
HRH2	ENST00000624694.2	n.994C>G		non_coding_transcript_exon_variant	1/3	5		ENSP00000490705.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461888 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

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 15, 2024

The c.994C>G (p.P332A) alteration is located in exon 1 (coding exon 1) of the HRH2 gene. This alteration results from a C to G substitution at nucleotide position 994, causing the proline (P) at amino acid position 332 to be replaced by an alanine (A). 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	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	8.1
DANN	Benign	0.70
DEOGEN2	Benign	0.082	.;.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.096	N
LIST_S2	Benign	0.57	T;T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.036	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;.;L
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.21	N;.;N
REVEL	Benign	0.039
Sift	Benign	0.38	T;.;T
Sift4G	Benign	0.48	T;.;T
Polyphen		0.0	.;.;B
Vest4		0.097
MutPred		0.20		Loss of glycosylation at P332 (P = 0.0174);Loss of glycosylation at P332 (P = 0.0174);Loss of glycosylation at P332 (P = 0.0174);
MVP		0.36
MPC		0.82
ClinPred		0.024	T
GERP RS		-0.89
Varity_R		0.021
gMVP		0.12

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: rs1756088661; hg19: chr5-175111230;