9-132230577-A-G

Variant names:

• chr9-132230577-A-G
• rs4962173
• NM_032536.4:c.1036A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032536.4(NTNG2):​c.1036A>G​(p.Thr346Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.995 in 1,604,494 control chromosomes in the GnomAD database, including 794,650 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 1.0 (75602 hom., cov: 33)
  • Exomes 𝑓: 1.0 (719048 hom.)
• Consequence: NTNG2 NM_032536.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.38

Genes affected

NTNG2 (HGNC:14288): (netrin G2) Predicted to be involved in several processes, including basement membrane assembly; cell morphogenesis involved in differentiation; and regulation of cell projection organization. Located in Flemming body; intercellular bridge; and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.0301176E-7).
• BP6: Variant 9-132230577-A-G is Benign according to our data. Variant chr9-132230577-A-G is described in ClinVar as [Benign]. Clinvar id is 1327005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.991 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTNG2	NM_032536.4	c.1036A>G	p.Thr346Ala	missense_variant	Exon 5 of 8	ENST00000393229.4	NP_115925.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTNG2	ENST00000393229.4	c.1036A>G	p.Thr346Ala	missense_variant	Exon 5 of 8	1	NM_032536.4	ENSP00000376921.3

Frequencies

GnomAD3 genomes AF: 0.996 AC: 151620 AN: 152158 Hom.: 75543 Cov.: 33

Gnomad AFR AF: 0.999

Gnomad AMI AF: 1.00

Gnomad AMR AF: 1.00

Gnomad ASJ AF: 0.999

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 0.987

Gnomad MID AF: 1.00

Gnomad NFE AF: 0.995

Gnomad OTH AF: 0.998

GnomAD2 exomes AF: 0.996 AC: 231277 AN: 232150 AF XY: 0.996

Gnomad AFR exome AF: 0.999

Gnomad AMR exome AF: 0.999

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.990

Gnomad NFE exome AF: 0.994

Gnomad OTH exome AF: 0.997

GnomAD4 exome AF: 0.995 AC: 1445130 AN: 1452218 Hom.: 719048 Cov.: 54 AF XY: 0.995 AC XY: 717988 AN XY: 721384

African (AFR) AF: 0.999 AC: 33355 AN: 33386

American (AMR) AF: 0.999 AC: 43584 AN: 43614

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 25867 AN: 25872

East Asian (EAS) AF: 1.00 AC: 39458 AN: 39462

South Asian (SAS) AF: 1.00 AC: 84203 AN: 84244

European-Finnish (FIN) AF: 0.990 AC: 51884 AN: 52434

Middle Eastern (MID) AF: 1.00 AC: 5750 AN: 5750

European-Non Finnish (NFE) AF: 0.994 AC: 1101268 AN: 1107486

Other (OTH) AF: 0.997 AC: 59761 AN: 59970

GnomAD4 genome AF: 0.996 AC: 151738 AN: 152276 Hom.: 75602 Cov.: 33 AF XY: 0.996 AC XY: 74175 AN XY: 74454

African (AFR) AF: 0.999 AC: 41516 AN: 41554

American (AMR) AF: 1.00 AC: 15301 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.999 AC: 3468 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5152 AN: 5152

South Asian (SAS) AF: 1.00 AC: 4829 AN: 4830

European-Finnish (FIN) AF: 0.987 AC: 10483 AN: 10618

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 0.995 AC: 67676 AN: 68024

Other (OTH) AF: 0.998 AC: 2109 AN: 2114

Alfa AF: 0.996 Hom.: 211127

Bravo AF: 0.997

TwinsUK AF: 0.994 AC: 3687

ALSPAC AF: 0.992 AC: 3825

ESP6500AA AF: 0.999 AC: 4398

ESP6500EA AF: 0.996 AC: 8561

ExAC AF: 0.993 AC: 119373

Asia WGS AF: 1.00 AC: 3478 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurodevelopmental disorder with behavioral abnormalities, absent speech, and hypotonia Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.043
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	16
DANN	Benign	0.20
DEOGEN2	Benign	0.058	.;T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.0047	N
LIST_S2	Benign	0.035	T;T
MetaRNN	Benign	6.0e-7	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.85	N;N
PhyloP100		2.4
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	1.1	N;N
REVEL	Benign	0.066
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	.;B
Vest4		0.043
MPC		0.92
ClinPred		0.0026	T
GERP RS		5.1
Varity_R		0.035
gMVP		0.32
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs4962173; hg19: chr9-135105964; COSMIC: COSV100647905;