rs772811573

chr11-64713030-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_015080.4(NRXN2):c.670C>T(p.Pro224Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000419 in 1,457,412 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000039 (0 hom.)
• Consequence: NRXN2 NM_015080.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.86

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.046080053).
• BS2: High AC in GnomAd at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRXN2	NM_015080.4	c.670C>T	p.Pro224Ser	missense_variant	2/23	ENST00000265459.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRXN2	ENST00000265459.11	c.670C>T	p.Pro224Ser	missense_variant	2/23	5	NM_015080.4	P4

Frequencies

GnomAD3 genomes AF: 0.0000724 AC: 11 AN: 151958 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000682 AC: 5 AN: 73352 Hom.: 0 AF XY: 0.0000730 AC XY: 3 AN XY: 41098

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000143

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000747

Gnomad OTH exome AF: 0.000437

GnomAD4 exome AF: 0.0000391 AC: 51 AN: 1305346 Hom.: 0 Cov.: 29 AF XY: 0.0000390 AC XY: 25 AN XY: 640566

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000464

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000157

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000336

Gnomad4 OTH exome AF: 0.0000556

GnomAD4 genome AF: 0.0000658 AC: 10 AN: 152066 Hom.: 0 Cov.: 34 AF XY: 0.0000404 AC XY: 3 AN XY: 74340

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000155 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.000234 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 22, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 10, 2022	The c.670C>T (p.P224S) alteration is located in exon 2 (coding exon 1) of the NRXN2 gene. This alteration results from a C to T substitution at nucleotide position 670, causing the proline (P) at amino acid position 224 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	22
Dann	Benign	0.94
DEOGEN2	Benign	0.0037	T;.;T;.
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.79	D
M_CAP	Pathogenic	0.74	D
MetaRNN	Benign	0.046	T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-0.26	N;N;N;.
MutationTaster	Benign	0.89	N;N;N;N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	0.29	N;N;N;N
REVEL	Benign	0.098
Sift	Benign	0.61	T;T;T;T
Sift4G	Uncertain	0.0050	D;D;D;D
Polyphen		0.073	B;B;B;.
Vest4		0.17
MutPred		0.50		Gain of glycosylation at P224 (P = 0.0225);Gain of glycosylation at P224 (P = 0.0225);Gain of glycosylation at P224 (P = 0.0225);Gain of glycosylation at P224 (P = 0.0225);
MVP		0.082
MPC		0.62
ClinPred		0.058	T
GERP RS		3.3
Varity_R		0.073
gMVP		0.31

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: rs772811573; hg19: chr11-64480502;