2-168860825-C-T

Variant names:

• chr2-168860825-C-T
• rs143019304
• NM_001039724.4:c.1210C>T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_001039724.4(NOSTRIN):​c.1210C>T​(p.Arg404Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,613,060 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00097 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (2 hom.)
• Consequence: NOSTRIN NM_001039724.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.69

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 Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 2-168860825-C-T is Benign according to our data. Variant chr2-168860825-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 790256.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOSTRIN	NM_001039724.4	c.1210C>T	p.Arg404Trp	missense_variant	Exon 14 of 16	ENST00000317647.12	NP_001034813.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOSTRIN	ENST00000317647.12	c.1210C>T	p.Arg404Trp	missense_variant	Exon 14 of 16	1	NM_001039724.4	ENSP00000318921.7

Frequencies

GnomAD3 genomes AF: 0.000967 AC: 147 AN: 152062 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00147

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000846 AC: 211 AN: 249446 Hom.: 1 AF XY: 0.000865 AC XY: 117 AN XY: 135332

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.00606

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.000621

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000954

Gnomad OTH exome AF: 0.000826

GnomAD4 exome AF: 0.00105 AC: 1533 AN: 1460880 Hom.: 2 Cov.: 30 AF XY: 0.00110 AC XY: 800 AN XY: 726830

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.00578

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000522

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.00112

Gnomad4 OTH exome AF: 0.000977

GnomAD4 genome AF: 0.000966 AC: 147 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.000874 AC XY: 65 AN XY: 74398

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00147

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00140 Hom.: 1

Bravo AF: 0.000801

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000816 AC: 3

ESP6500EA AF: 0.00122 AC: 10

ExAC AF: 0.000861 AC: 104

EpiCase AF: 0.00125

EpiControl AF: 0.00130

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Sep 16, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1381C>T (p.R461W) alteration is located in exon 19 (coding exon 15) of the NOSTRIN gene. This alteration results from a C to T substitution at nucleotide position 1381, causing the arginine (R) at amino acid position 461 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Jul 20, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.081	.;.;T;.;.;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.95	.;D;D;.;D;D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.013	T;T;T;T;T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.5	.;.;M;.;.;.
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.9	N;N;N;N;N;N
REVEL	Benign	0.23
Sift	Uncertain	0.0040	D;D;D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D;D;D
Polyphen		1.0, 1.0, 0.99	.;.;D;D;D;D
Vest4		0.47
MVP		0.80
MPC		0.37
ClinPred		0.049	T
GERP RS		5.8
Varity_R		0.22
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.29		Position offset: -30

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs143019304; hg19: chr2-169717335; COSMIC: COSV99048191; COSMIC: COSV99048191;