chr12-122702692-A-G

Variant names:

• chr12-122702692-A-G
• rs676823
• NM_177551.4:c.592T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_177551.4(HCAR2):​c.592T>C​(p.Phe198Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 0.00044 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000038 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HCAR2 NM_177551.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.225
• Publications: 12 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011788726).

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.592T>C	p.Phe198Leu	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.592T>C	p.Phe198Leu	missense	Exon 1 of 1	ENSP00000375066.2
	ENSG00000256249	ENST00000543611.1	TSL:4	n.401+1362A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000438 AC: 60 AN: 136962 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000213

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000507

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000625

Gnomad SAS AF: 0.000448

Gnomad FIN AF: 0.000526

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000560

Gnomad OTH AF: 0.000535

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 250692 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0000468

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000383 AC: 53 AN: 1383966 Hom.: 0 Cov.: 35 AF XY: 0.0000419 AC XY: 29 AN XY: 691390

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

African (AFR) AF: 0.00 AC: 0 AN: 32472

American (AMR) AF: 0.0000225 AC: 1 AN: 44456

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25402

East Asian (EAS) AF: 0.00 AC: 0 AN: 39272

South Asian (SAS) AF: 0.00 AC: 0 AN: 85478

European-Finnish (FIN) AF: 0.0000976 AC: 5 AN: 51216

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5626

European-Non Finnish (NFE) AF: 0.0000403 AC: 42 AN: 1042096

Other (OTH) AF: 0.0000863 AC: 5 AN: 57948

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000000787703), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000438 AC: 60 AN: 137070 Hom.: 0 Cov.: 31 AF XY: 0.000523 AC XY: 35 AN XY: 66924

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

African (AFR) AF: 0.000212 AC: 8 AN: 37682

American (AMR) AF: 0.000506 AC: 7 AN: 13834

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3112

East Asian (EAS) AF: 0.000626 AC: 3 AN: 4792

South Asian (SAS) AF: 0.000449 AC: 2 AN: 4454

European-Finnish (FIN) AF: 0.000526 AC: 5 AN: 9510

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 258

European-Non Finnish (NFE) AF: 0.000560 AC: 34 AN: 60732

Other (OTH) AF: 0.000529 AC: 1 AN: 1892

⚠️ 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: 0.00207 Hom.: 0

ExAC AF: 0.0000824 AC: 10

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	0.0031	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	17
DANN	Benign	0.95
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.23
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.29
Sift	Benign	0.15	T
Sift4G	Benign	0.14	T
Polyphen		0.19	B
Vest4		0.099
MutPred		0.16		Loss of helix (P = 0.2022)
MVP		0.54
MPC		0.98
ClinPred		0.17	T
GERP RS		1.2
Varity_R		0.24
gMVP		0.18
Mutation Taster		=82/18	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: rs676823; hg19: chr12-123187239; COSMIC: COSV61024303;