9-132197994-G-A

Variant names:

• chr9-132197994-G-A
• rs1589440982
• NM_032536.4:c.242G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_032536.4(NTNG2):​c.242G>A​(p.Cys81Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NTNG2 NM_032536.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 10.0
• Publications: 1 publications found

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]

NTNG2 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with behavioral abnormalities, absent speech, and hypotonia

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978
• PP5: Variant 9-132197994-G-A is Pathogenic according to our data. Variant chr9-132197994-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 691559.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032536.4. 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
	NTNG2	NM_032536.4	MANE Select	c.242G>A	p.Cys81Tyr	missense	Exon 3 of 8	NP_115925.2	Q96CW9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTNG2	ENST00000393229.4	TSL:1 MANE Select	c.242G>A	p.Cys81Tyr	missense	Exon 3 of 8	ENSP00000376921.3	Q96CW9-1
	NTNG2	ENST00000946492.1		c.242G>A	p.Cys81Tyr	missense	Exon 3 of 11	ENSP00000616551.1
	NTNG2	ENST00000922385.1		c.242G>A	p.Cys81Tyr	missense	Exon 4 of 9	ENSP00000592444.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Neurodevelopmental disorder (1)
1	-	-	Neurodevelopmental disorder with behavioral abnormalities, absent speech, and hypotonia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		10
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-10	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.89		Gain of phosphorylation at C81 (P = 0.0187)
MVP		0.98
MPC		2.6
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.96
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs1589440982; hg19: chr9-135073381;