2-168834321-G-A

Position:

• chr2-168834321-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001039724.4(NOSTRIN):​c.500G>A​(p.Arg167Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00905 in 872,468 control chromosomes in the GnomAD database, including 420 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (260 hom., cov: 31)
  • Exomes 𝑓: 0.0041 (160 hom.)
• Consequence: NOSTRIN NM_001039724.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.51

Genes affected

NOSTRIN (HGNC:20203): (nitric oxide synthase trafficking) Nitric oxide (NO) is a potent mediator in biologic processes such as neurotransmission, inflammatory response, and vascular homeostasis. NOSTRIN binds the enzyme responsible for NO production, endothelial NO synthase (ENOS; MIM 163729), and triggers the translocation of ENOS from the plasma membrane to vesicle-like subcellular structures, thereby attenuating ENOS-dependent NO production.[supplied by OMIM, Apr 2004]

SPC25 (HGNC:24031): (SPC25 component of NDC80 kinetochore complex) This gene encodes a protein that may be involved in kinetochore-microtubule interaction and spindle checkpoint activity. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012488365).
• BP6: Variant 2-168834321-G-A is Benign according to our data. Variant chr2-168834321-G-A is described in ClinVar as [Benign]. Clinvar id is 767829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOSTRIN	NM_001039724.4	c.500G>A	p.Arg167Gln	missense_variant	7/16	ENST00000317647.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOSTRIN	ENST00000317647.12	c.500G>A	p.Arg167Gln	missense_variant	7/16	1	NM_001039724.4	P1

Frequencies

GnomAD3 genomes AF: 0.0326 AC: 4950 AN: 151992 Hom.: 255 Cov.: 31

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0129

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.0235

GnomAD3 exomes AF: 0.00808 AC: 2009 AN: 248756 Hom.: 118 AF XY: 0.00631 AC XY: 851 AN XY: 134972

Gnomad AFR exome AF: 0.118

Gnomad AMR exome AF: 0.00389

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000204

Gnomad OTH exome AF: 0.00232

GnomAD4 exome AF: 0.00407 AC: 2929 AN: 720358 Hom.: 160 Cov.: 0 AF XY: 0.00318 AC XY: 1224 AN XY: 384526

Gnomad4 AFR exome AF: 0.118

Gnomad4 AMR exome AF: 0.00485

Gnomad4 ASJ exome AF: 0.0000930

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000237

Gnomad4 FIN exome AF: 0.0000376

Gnomad4 NFE exome AF: 0.000138

Gnomad4 OTH exome AF: 0.00814

GnomAD4 genome AF: 0.0326 AC: 4966 AN: 152110 Hom.: 260 Cov.: 31 AF XY: 0.0312 AC XY: 2324 AN XY: 74388

Gnomad4 AFR AF: 0.113

Gnomad4 AMR AF: 0.0128

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.0232

Alfa AF: 0.00498 Hom.: 51

Bravo AF: 0.0376

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.108 AC: 439

ESP6500EA AF: 0.000238 AC: 2

ExAC AF: 0.00955 AC: 1155

Asia WGS AF: 0.00751 AC: 26 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.000297

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 06, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	18
DANN	Benign	0.85
DEOGEN2	Benign	0.00072	.;.;T;.;.;.;.
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.13	N
LIST_S2	Uncertain	0.86	.;D;D;.;D;D;D
MetaRNN	Benign	0.0012	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.4	N;N;N;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.65	N;N;N;N;N;N;N
REVEL	Benign	0.070
Sift	Benign	1.0	T;T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T
Polyphen		0.0030, 0.014	.;.;B;.;.;B;.
Vest4		0.090
MVP		0.33
MPC		0.093
ClinPred		0.0053	T
GERP RS		0.50
Varity_R		0.036
gMVP		0.019

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

Publications

LitVar

Other links and lift over

dbSNP: rs73969974; hg19: chr2-169690831;