chr2-165294040-A-AAATTT

Variant names:

• chr2-165294040-A-AAATTT
• rs780674346
• ENST00000283256.10:c.-147_-146insAATTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The ENST00000283256.10(SCN2A):​c.-147_-146insAATTT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000077 (0 hom., cov: 11)
  • Exomes 𝑓: 0.0000057 (0 hom.)
• Consequence: SCN2A ENST00000283256.10 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.275
• Publications: 1 publications found

Genes affected

SCN2A (HGNC:10588): (sodium voltage-gated channel alpha subunit 2) Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with four repeat domains, each of which is composed of six membrane-spanning segments, and one or more regulatory beta subunits. Voltage-gated sodium channels function in the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family. Allelic variants of this gene are associated with seizure disorders and autism spectrum disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]

SCN2A Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Illumina, ClinGen, PanelApp Australia
• developmental and epileptic encephalopathy, 11

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• episodic ataxia, type 9

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• seizures, benign familial infantile, 3

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• benign familial infantile epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• benign familial neonatal-infantile seizures

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Dravet syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• malignant migrating partial seizures of infancy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000283256.10. 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
	SCN2A	NM_001040142.2	MANE Select	c.-51-1733_-51-1732insAATTT		intron	N/A	NP_001035232.1	Q99250-1
	SCN2A	NM_001371246.1	MANE Plus Clinical	c.-51-1733_-51-1732insAATTT		intron	N/A	NP_001358175.1	Q99250-2
	SCN2A	NM_001040143.2		c.-51-1733_-51-1732insAATTT		intron	N/A	NP_001035233.1	Q99250-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN2A	ENST00000283256.10	TSL:1	c.-147_-146insAATTT		5_prime_UTR	Exon 1 of 27	ENSP00000283256.6	Q99250-1
	SCN2A	ENST00000375437.7	TSL:5 MANE Select	c.-51-1733_-51-1732insAATTT		intron	N/A	ENSP00000364586.2	Q99250-1
	SCN2A	ENST00000631182.3	TSL:5 MANE Plus Clinical	c.-51-1733_-51-1732insAATTT		intron	N/A	ENSP00000486885.1	Q99250-2

Frequencies

GnomAD3 genomes AF: 0.0000772 AC: 8 AN: 103642 Hom.: 0 Cov.: 11

Gnomad AFR AF: 0.0000361

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000227

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: 0.0000761

Gnomad OTH AF: 0.000743

GnomAD4 exome AF: 0.00000570 AC: 3 AN: 526700 Hom.: 0 Cov.: 0 AF XY: 0.00000817 AC XY: 2 AN XY: 244878

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

African (AFR) AF: 0.00 AC: 0 AN: 9788

American (AMR) AF: 0.00 AC: 0 AN: 658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3078

East Asian (EAS) AF: 0.00 AC: 0 AN: 2428

South Asian (SAS) AF: 0.00 AC: 0 AN: 10388

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 182

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 912

European-Non Finnish (NFE) AF: 0.00000622 AC: 3 AN: 482028

Other (OTH) AF: 0.00 AC: 0 AN: 17238

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000772 AC: 8 AN: 103678 Hom.: 0 Cov.: 11 AF XY: 0.0000835 AC XY: 4 AN XY: 47922

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

African (AFR) AF: 0.0000361 AC: 1 AN: 27710

American (AMR) AF: 0.000227 AC: 2 AN: 8824

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2632

East Asian (EAS) AF: 0.00 AC: 0 AN: 3310

South Asian (SAS) AF: 0.00 AC: 0 AN: 2928

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3462

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 178

European-Non Finnish (NFE) AF: 0.0000761 AC: 4 AN: 52552

Other (OTH) AF: 0.000741 AC: 1 AN: 1350

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000000000000230926), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Early Infantile Epileptic Encephalopathy, Autosomal Dominant (1)
-	1	-	Seizures, benign familial infantile, 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.28

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs780674346; hg19: chr2-166150550;