chr9-114330492-C-T

Variant names:

• chr9-114330492-C-T
• rs762265516
• NM_000608.4:c.173C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000608.4(ORM2):​c.173C>T​(p.Ser58Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,611,286 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: ORM2 NM_000608.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -5.16
• Publications: 1 publications found

Genes affected

ORM2 (HGNC:8499): (orosomucoid 2) This gene encodes a key acute phase plasma protein. Because of its increase due to acute inflammation, this protein is classified as an acute-phase reactant. The specific function of this protein has not yet been determined; however, it may be involved in aspects of immunosuppression. [provided by RefSeq, Jul 2008]

AKNA (HGNC:24108): (AT-hook transcription factor) Predicted to enable DNA binding activity. Involved in positive regulation of transcription by RNA polymerase II. Located in centrosome; cytosol; and nuclear lumen. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.044869065).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000608.4. 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
	ORM2	NM_000608.4	MANE Select	c.173C>T	p.Ser58Leu	missense	Exon 2 of 6	NP_000599.1	P19652

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ORM2	ENST00000431067.4	TSL:1 MANE Select	c.173C>T	p.Ser58Leu	missense	Exon 2 of 6	ENSP00000394936.2	P19652
	ORM2	ENST00000893195.1		c.173C>T	p.Ser58Leu	missense	Exon 2 of 7	ENSP00000563254.1
	ORM2	ENST00000893198.1		c.173C>T	p.Ser58Leu	missense	Exon 2 of 6	ENSP00000563257.1

Frequencies

GnomAD3 genomes AF: 0.0000332 AC: 5 AN: 150468 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000501

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250876 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000192 AC: 28 AN: 1460818 Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13 AN XY: 726790

African (AFR) AF: 0.0000305 AC: 1 AN: 32754

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

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

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86238

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1111750

Other (OTH) AF: 0.0000166 AC: 1 AN: 60346

GnomAD4 genome AF: 0.0000332 AC: 5 AN: 150468 Hom.: 0 Cov.: 29 AF XY: 0.0000272 AC XY: 2 AN XY: 73494

African (AFR) AF: 0.0000501 AC: 2 AN: 39960

American (AMR) AF: 0.000132 AC: 2 AN: 15196

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67956

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

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	0.14
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.0030
DANN	Benign	0.88
DEOGEN2	Benign	0.024	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0026	N
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.045	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PhyloP100		-5.2
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.021
Sift	Benign	0.17	T
Sift4G	Benign	0.39	T
Polyphen		0.044	B
Vest4		0.14
MutPred		0.43		Loss of disorder (P = 0.0094)
MVP		0.16
MPC		1.4
ClinPred		0.046	T
GERP RS		-6.2
Varity_R		0.091
gMVP		0.35
Mutation Taster		=81/19	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: rs762265516; hg19: chr9-117092772;