rs2454727

Variant names:

• chr12-122702333-C-T
• rs2454727
• NM_177551.4:c.951G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_177551.4(HCAR2):​c.951G>A​(p.Met317Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (3 hom., cov: 32)
  • Exomes 𝑓: 0.12 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: HCAR2 NM_177551.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -4.12
• Publications: 21 publications found

Genes affected

HCAR2 (HGNC:24827): (hydroxycarboxylic acid receptor 2) Predicted to enable nicotinic acid receptor activity. Involved in neutrophil apoptotic process and positive regulation of neutrophil apoptotic process. Located in cell junction and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000256249 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018282831).
• BP6: Variant 12-122702333-C-T is Benign according to our data. Variant chr12-122702333-C-T is described in ClinVar as Benign. ClinVar VariationId is 770415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCAR2	NM_177551.4	c.951G>A	p.Met317Ile	missense_variant	Exon 1 of 1	ENST00000328880.6	NP_808219.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCAR2	ENST00000328880.6	c.951G>A	p.Met317Ile	missense_variant	Exon 1 of 1	6	NM_177551.4	ENSP00000375066.2
ENSG00000256249	ENST00000543611.1	n.401+1003C>T		intron_variant	Intron 2 of 2	4

Frequencies

GnomAD3 genomes AF: 0.228 AC: 33186 AN: 145294 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.324

Gnomad AMR AF: 0.224

Gnomad ASJ AF: 0.314

Gnomad EAS AF: 0.0270

Gnomad SAS AF: 0.197

Gnomad FIN AF: 0.256

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.301

Gnomad OTH AF: 0.239

GnomAD2 exomes AF: 0.106 AC: 20791 AN: 196912 AF XY: 0.106

Gnomad AFR exome AF: 0.0564

Gnomad AMR exome AF: 0.0867

Gnomad ASJ exome AF: 0.109

Gnomad EAS exome AF: 0.0115

Gnomad FIN exome AF: 0.0976

Gnomad NFE exome AF: 0.150

Gnomad OTH exome AF: 0.142

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.121 AC: 140790 AN: 1166210 Hom.: 1 Cov.: 42 AF XY: 0.124 AC XY: 72600 AN XY: 583724

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0545 AC: 1709 AN: 31380

American (AMR) AF: 0.108 AC: 4252 AN: 39338

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 4811 AN: 22348

East Asian (EAS) AF: 0.0201 AC: 789 AN: 39210

South Asian (SAS) AF: 0.130 AC: 9830 AN: 75844

European-Finnish (FIN) AF: 0.209 AC: 9399 AN: 44916

Middle Eastern (MID) AF: 0.150 AC: 697 AN: 4642

European-Non Finnish (NFE) AF: 0.119 AC: 101856 AN: 857572

Other (OTH) AF: 0.146 AC: 7447 AN: 50960

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.228 AC: 33180 AN: 145410 Hom.: 3 Cov.: 32 AF XY: 0.224 AC XY: 15850 AN XY: 70798

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.124 AC: 4937 AN: 39720

American (AMR) AF: 0.223 AC: 3266 AN: 14630

Ashkenazi Jewish (ASJ) AF: 0.314 AC: 1039 AN: 3314

East Asian (EAS) AF: 0.0268 AC: 138 AN: 5144

South Asian (SAS) AF: 0.195 AC: 909 AN: 4652

European-Finnish (FIN) AF: 0.256 AC: 2576 AN: 10052

Middle Eastern (MID) AF: 0.321 AC: 93 AN: 290

European-Non Finnish (NFE) AF: 0.301 AC: 19464 AN: 64724

Other (OTH) AF: 0.235 AC: 470 AN: 1996

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.240 Hom.: 4

ExAC AF: 0.184 AC: 22340

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 13, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25363768) -

Mar 28, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.0030
DANN	Benign	0.69
DEOGEN2	Benign	0.064	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		-4.1
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.035
Sift	Benign	0.45	T
Sift4G	Benign	0.42	T
Polyphen		0.0	B
Vest4		0.017
MutPred		0.11		Gain of methylation at K316 (P = 0.024);
MPC		0.80
ClinPred		0.0070	T
GERP RS		-11
Varity_R		0.047
gMVP		0.14
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs2454727; hg19: chr12-123186880; COSMIC: COSV61024117;