12-122702767-C-T

Variant names:

• chr12-122702767-C-T
• rs141052038
• NM_177551.4:c.517G>A

Variant summary

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

The NM_177551.4(HCAR2):​c.517G>A​(p.Gly173Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00275 in 1,613,814 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G173C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0022 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0028 (14 hom.)
• Consequence: HCAR2 NM_177551.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -6.91
• Publications: 5 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=0.004376948).
• BS2: High Homozygotes in GnomAd4 at 3 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCAR2	NM_177551.4	MANE Select	c.517G>A	p.Gly173Ser	missense	Exon 1 of 1	NP_808219.1	Q8TDS4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCAR2	ENST00000328880.6	TSL:6 MANE Select	c.517G>A	p.Gly173Ser	missense	Exon 1 of 1	ENSP00000375066.2	Q8TDS4
	ENSG00000256249	ENST00000543611.1	TSL:4	n.401+1437C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00216 AC: 329 AN: 152142 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00388

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00172 AC: 432 AN: 251316 AF XY: 0.00164

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00139

Gnomad NFE exome AF: 0.00305

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.00281 AC: 4105 AN: 1461554 Hom.: 14 Cov.: 34 AF XY: 0.00282 AC XY: 2047 AN XY: 727086

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

African (AFR) AF: 0.000687 AC: 23 AN: 33474

American (AMR) AF: 0.000872 AC: 39 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.000464 AC: 40 AN: 86250

European-Finnish (FIN) AF: 0.00187 AC: 100 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00336 AC: 3737 AN: 1111698

Other (OTH) AF: 0.00268 AC: 162 AN: 60392

⚠️ 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: 0.00216 AC: 329 AN: 152260 Hom.: 3 Cov.: 31 AF XY: 0.00184 AC XY: 137 AN XY: 74442

African (AFR) AF: 0.000722 AC: 30 AN: 41546

American (AMR) AF: 0.000589 AC: 9 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00226 AC: 24 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00388 AC: 264 AN: 68024

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000430 Hom.: 0

Bravo AF: 0.00187

ExAC AF: 0.00189 AC: 229

EpiCase AF: 0.00338

EpiControl AF: 0.00338

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.0010
DANN	Benign	0.49
DEOGEN2	Benign	0.039	T
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.0043	N
LIST_S2	Benign	0.19	T
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.70	N
PhyloP100		-6.9
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.90	N
REVEL	Benign	0.048
Sift	Benign	0.30	T
Sift4G	Benign	0.81	T
Polyphen		0.0050	B
Vest4		0.053
MVP		0.061
MPC		0.72
ClinPred		0.022	T
GERP RS		-11
Varity_R		0.050
gMVP		0.089
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs141052038; hg19: chr12-123187314; COSMIC: COSV100186714;