12-122702353-G-A

Variant names:

• chr12-122702353-G-A
• rs7314976
• NM_177551.4:c.931C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_177551.4(HCAR2):​c.931C>T​(p.Arg311Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0975 in 149,072 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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: 𝑓 0.097 (2 hom., cov: 32)
  • Exomes 𝑓: 0.052 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HCAR2 NM_177551.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.825
• Publications: 14 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016220659).
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_177551.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCAR2	NM_177551.4	MANE Select	c.931C>T	p.Arg311Cys	missense	Exon 1 of 1	NP_808219.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCAR2	ENST00000328880.6	TSL:6 MANE Select	c.931C>T	p.Arg311Cys	missense	Exon 1 of 1	ENSP00000375066.2
	ENSG00000256249	ENST00000543611.1	TSL:4	n.401+1023G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0976 AC: 14536 AN: 148952 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0238

Gnomad AMI AF: 0.157

Gnomad AMR AF: 0.116

Gnomad ASJ AF: 0.0956

Gnomad EAS AF: 0.000961

Gnomad SAS AF: 0.0678

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.0478

Gnomad NFE AF: 0.144

Gnomad OTH AF: 0.0877

GnomAD2 exomes AF: 0.0389 AC: 8582 AN: 220734 AF XY: 0.0378

Gnomad AFR exome AF: 0.00873

Gnomad AMR exome AF: 0.0465

Gnomad ASJ exome AF: 0.0278

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.0333

Gnomad NFE exome AF: 0.0550

Gnomad OTH exome AF: 0.0552

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0521 AC: 66110 AN: 1268016 Hom.: 0 Cov.: 36 AF XY: 0.0525 AC XY: 33313 AN XY: 634620

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

African (AFR) AF: 0.0102 AC: 337 AN: 32910

American (AMR) AF: 0.0586 AC: 2354 AN: 40160

Ashkenazi Jewish (ASJ) AF: 0.0638 AC: 1558 AN: 24416

East Asian (EAS) AF: 0.000252 AC: 10 AN: 39694

South Asian (SAS) AF: 0.0405 AC: 3311 AN: 81730

European-Finnish (FIN) AF: 0.0960 AC: 4646 AN: 48386

Middle Eastern (MID) AF: 0.0243 AC: 134 AN: 5516

European-Non Finnish (NFE) AF: 0.0536 AC: 50407 AN: 940688

Other (OTH) AF: 0.0615 AC: 3353 AN: 54516

⚠️ 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 AF: 0.0975 AC: 14530 AN: 149072 Hom.: 2 Cov.: 32 AF XY: 0.0949 AC XY: 6901 AN XY: 72706

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

African (AFR) AF: 0.0237 AC: 978 AN: 41204

American (AMR) AF: 0.115 AC: 1720 AN: 14914

Ashkenazi Jewish (ASJ) AF: 0.0956 AC: 325 AN: 3400

East Asian (EAS) AF: 0.000963 AC: 5 AN: 5190

South Asian (SAS) AF: 0.0680 AC: 323 AN: 4748

European-Finnish (FIN) AF: 0.129 AC: 1321 AN: 10242

Middle Eastern (MID) AF: 0.0445 AC: 13 AN: 292

European-Non Finnish (NFE) AF: 0.144 AC: 9527 AN: 66124

Other (OTH) AF: 0.0858 AC: 177 AN: 2062

⚠️ 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: 0.115 Hom.: 1

ExAC AF: 0.0811 AC: 9849

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.82
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.055
Sift	Benign	0.12	T
Sift4G	Benign	0.11	T
Polyphen		0.084	B
Vest4		0.084
MPC		0.99
ClinPred		0.0063	T
GERP RS		3.3
Varity_R		0.079
gMVP		0.42
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs7314976; hg19: chr12-123186900; COSMIC: COSV61024824;