5-175684159-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM2 PP2 BP4_Strong BP6_Moderate

The NM_001367711.1(HRH2):c.926A>G(p.Asn309Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: HRH2 NM_001367711.1 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.886

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 -3 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=0.03839633).
• BP6: Variant 5-175684159-A-G is Benign according to our data. Variant chr5-175684159-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2324737.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HRH2	NM_001367711.1	c.926A>G	p.Asn309Ser	missense_variant	2/3	ENST00000636584.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HRH2	ENST00000636584.2	c.926A>G	p.Asn309Ser	missense_variant	2/3	3	NM_001367711.1	P1
HRH2	ENST00000377291.2	c.926A>G	p.Asn309Ser	missense_variant	2/3	1
HRH2	ENST00000624694.2	c.926A>G	p.Asn309Ser	missense_variant, NMD_transcript_variant	1/3	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251450 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135896

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461880 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727238

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: 0.0000331

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	1.8
Dann	Benign	0.15
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0053	N
LIST_S2	Benign	0.42	T;T;T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.038	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N;.;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.30	N;.;N
REVEL	Benign	0.030
Sift	Benign	1.0	T;.;T
Sift4G	Benign	0.96	T;.;T
Polyphen		0.0	.;.;B
Vest4		0.042
MutPred		0.29		Gain of catalytic residue at N309 (P = 0.0496);Gain of catalytic residue at N309 (P = 0.0496);Gain of catalytic residue at N309 (P = 0.0496);
MVP		0.37
MPC		0.67
ClinPred		0.076	T
GERP RS		0.67
Varity_R		0.032
gMVP		0.057

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs772022828; hg19: chr5-175111162;