chr11-64607521-C-T

Variant names:

• chr11-64607521-C-T
• rs748840734
• NM_015080.4:c.4814G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_015080.4(NRXN2):​c.4814G>A​(p.Gly1605Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000488 in 1,433,634 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1605R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: NRXN2 NM_015080.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.477
• Publications: 0 publications found

Genes affected

NRXN2 (HGNC:8009): (neurexin 2) This gene encodes a member of the neurexin gene family. The products of these genes function as cell adhesion molecules and receptors in the vertebrate nervous system. These genes utilize two promoters. The majority of transcripts are produced from the upstream promoter and encode alpha-neurexin isoforms while a smaller number of transcripts are produced from the downstream promoter and encode beta-neuresin isoforms. The alpha-neurexins contain epidermal growth factor-like (EGF-like) sequences and laminin G domains, and have been shown to interact with neurexophilins. The beta-neurexins lack EGF-like sequences and contain fewer laminin G domains than alpha-neurexins. Alternative splicing and the use of alternative promoters may generate thousands of transcript variants (PMID: 12036300, PMID: 11944992).[provided by RefSeq, Jun 2010]

NRXN2 Gene-Disease associations (from GenCC):

• autism

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, G2P
• neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.047447383).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015080.4. 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
	NRXN2	NM_015080.4	MANE Select	c.4814G>A	p.Gly1605Asp	missense	Exon 23 of 23	NP_055895.1	Q9P2S2-1
	NRXN2	NM_138732.3		c.4604G>A	p.Gly1535Asp	missense	Exon 20 of 20	NP_620060.1	Q9P2S2-2
	NRXN2	NM_138734.3		c.1676G>A	p.Gly559Asp	missense	Exon 7 of 7	NP_620063.1	P58401-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRXN2	ENST00000265459.11	TSL:5 MANE Select	c.4814G>A	p.Gly1605Asp	missense	Exon 23 of 23	ENSP00000265459.5	Q9P2S2-1
	NRXN2	ENST00000704782.1		c.4823G>A	p.Gly1608Asp	missense	Exon 22 of 22	ENSP00000516031.1	A0A994J5C3
	NRXN2	ENST00000377559.7	TSL:1	c.4604G>A	p.Gly1535Asp	missense	Exon 20 of 20	ENSP00000366782.3	Q9P2S2-2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.0000344 AC: 7 AN: 203304 AF XY: 0.0000355

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000127

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000832

Gnomad NFE exome AF: 0.0000225

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000488 AC: 7 AN: 1433634 Hom.: 0 Cov.: 33 AF XY: 0.00000563 AC XY: 4 AN XY: 711044

African (AFR) AF: 0.00 AC: 0 AN: 33134

American (AMR) AF: 0.0000701 AC: 3 AN: 42810

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25714

East Asian (EAS) AF: 0.00 AC: 0 AN: 39098

South Asian (SAS) AF: 0.00 AC: 0 AN: 84946

European-Finnish (FIN) AF: 0.0000239 AC: 1 AN: 41880

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 9.08e-7 AC: 1 AN: 1100960

Other (OTH) AF: 0.0000337 AC: 2 AN: 59398

GnomAD4 genome Cov.: 30

Alfa AF: 0.0000509 Hom.: 0

ExAC AF: 0.0000170 AC: 2

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	0.11
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.096	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.58	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.047	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.48
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.10
Sift	Benign	0.85	T
Sift4G	Benign	0.64	T
Polyphen		0.012	B
Vest4		0.10
MutPred		0.10		Gain of solvent accessibility (P = 0.1014)
MVP		0.28
MPC		1.3
ClinPred		0.041	T
GERP RS		3.8
Varity_R		0.10
gMVP		0.39
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs748840734; hg19: chr11-64374993;