rs2274446

Variant names:

• chr1-208079111-C-A
• rs2274446
• NM_025179.4:c.2586+149G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-208079111-C-A
• chr1-208079111-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_025179.4(PLXNA2):​c.2586+149G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000208 in 481,854 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PLXNA2 NM_025179.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.583
• Publications: 0 publications found

Genes affected

PLXNA2 (HGNC:9100): (plexin A2) This gene encodes a member of the plexin-A family of semaphorin co-receptors. Semaphorins are a large family of secreted or membrane-bound proteins that mediate repulsive effects on axon pathfinding during nervous system development. A subset of semaphorins are recognized by plexin-A/neuropilin transmembrane receptor complexes, triggering a cellular signal transduction cascade that leads to axon repulsion. This plexin-A family member is thought to transduce signals from semaphorin-3A and -3C. [provided by RefSeq, Jul 2008]

PLXNA2 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD, AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLXNA2	NM_025179.4	c.2586+149G>T		intron_variant	Intron 12 of 31	ENST00000367033.4	NP_079455.3
PLXNA2	XM_005273164.4	c.2631+149G>T		intron_variant	Intron 12 of 32		XP_005273221.1
PLXNA2	XM_005273165.5	c.2631+149G>T		intron_variant	Intron 12 of 30		XP_005273222.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLXNA2	ENST00000367033.4	c.2586+149G>T		intron_variant	Intron 12 of 31	1	NM_025179.4	ENSP00000356000.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000208 AC: 1 AN: 481854 Hom.: 0 AF XY: 0.00000400 AC XY: 1 AN XY: 249814

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000761 AC: 1 AN: 13136

American (AMR) AF: 0.00 AC: 0 AN: 18542

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13460

East Asian (EAS) AF: 0.00 AC: 0 AN: 30974

South Asian (SAS) AF: 0.00 AC: 0 AN: 41870

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42982

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2068

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 292218

Other (OTH) AF: 0.00 AC: 0 AN: 26604

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.63
DANN	Benign	0.76
PhyloP100		-0.58

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: rs2274446; hg19: chr1-208252456;