11-64607816-G-T

Variant names:

• chr11-64607816-G-T
• rs749398433
• NM_015080.4:c.4519C>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_015080.4(NRXN2):​c.4519C>A​(p.Pro1507Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000375 in 1,601,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: NRXN2 NM_015080.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.01

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19887564).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRXN2	NM_015080.4	c.4519C>A	p.Pro1507Thr	missense_variant	Exon 23 of 23	ENST00000265459.11	NP_055895.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRXN2	ENST00000265459.11	c.4519C>A	p.Pro1507Thr	missense_variant	Exon 23 of 23	5	NM_015080.4	ENSP00000265459.5
NRXN2	ENST00000704782.1	c.4528C>A	p.Pro1510Thr	missense_variant	Exon 22 of 22			ENSP00000516031.1
NRXN2	ENST00000704781.1	c.4262-316C>A		intron_variant	Intron 21 of 21			ENSP00000516029.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152086 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000345 AC: 5 AN: 1449710 Hom.: 0 Cov.: 34 AF XY: 0.00000278 AC XY: 2 AN XY: 719884

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000119

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152086 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74294

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Benign	-0.0011	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.52	D;T;.;T;.
Eigen	Benign	0.15
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;.;D;D;D
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.20	T;T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.1	.;L;.;L;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.8	D;N;N;N;N
REVEL	Benign	0.21
Sift	Uncertain	0.028	D;T;T;T;T
Sift4G	Uncertain	0.034	D;D;D;D;D
Polyphen		1.0	D;B;D;B;.
Vest4		0.27
MutPred		0.21		.;Gain of glycosylation at P1507 (P = 0.0153);.;Gain of glycosylation at P1507 (P = 0.0153);.;
MVP		0.15
MPC		1.2
ClinPred		0.70	D
GERP RS		3.9
Varity_R		0.15
gMVP		0.28

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: rs749398433; hg19: chr11-64375288;