2-165294010-TAAAAAAAAAAAAAAAAAA-TAAAAAAAAAAAAAAA

Variant names:

• chr2-165294010-TAAA-T
• rs67417831
• NM_001040142.2:c.-51-1737_-51-1735delAAA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001040142.2(SCN2A):​c.-51-1737_-51-1735delAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0484 in 150,412 control chromosomes in the GnomAD database, including 24 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0076 (1 hom., cov: 0)
  • Exomes 𝑓: 0.073 (23 hom.)
• Consequence: SCN2A NM_001040142.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.311
• Publications: 0 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 Submitted by: Illumina, ClinGen
• developmental and epileptic encephalopathy, 11

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 2-165294010-TAAA-T is Benign according to our data. Variant chr2-165294010-TAAA-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1703351.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.112 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040142.2. 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.-51-1737_-51-1735delAAA		intron	N/A	NP_001035232.1	Q99250-1
	SCN2A	NM_001371246.1	MANE Plus Clinical	c.-51-1737_-51-1735delAAA		intron	N/A	NP_001358175.1	Q99250-2
	SCN2A	NM_001040143.2		c.-51-1737_-51-1735delAAA		intron	N/A	NP_001035233.1	Q99250-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN2A	ENST00000375437.7	TSL:5 MANE Select	c.-51-1762_-51-1760delAAA		intron	N/A	ENSP00000364586.2	Q99250-1
	SCN2A	ENST00000631182.3	TSL:5 MANE Plus Clinical	c.-51-1762_-51-1760delAAA		intron	N/A	ENSP00000486885.1	Q99250-2
	SCN2A	ENST00000424833.5	TSL:1	c.-51-1762_-51-1760delAAA		intron	N/A	ENSP00000406454.2	F6U291

Frequencies

GnomAD3 genomes AF: 0.00760 AC: 425 AN: 55896 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.0109

Gnomad AMI AF: 0.00198

Gnomad AMR AF: 0.00328

Gnomad ASJ AF: 0.000505

Gnomad EAS AF: 0.0139

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00671

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00722

Gnomad OTH AF: 0.00315

GnomAD4 exome AF: 0.0726 AC: 6860 AN: 94506 Hom.: 23 AF XY: 0.0723 AC XY: 3278 AN XY: 45370

African (AFR) AF: 0.123 AC: 331 AN: 2692

American (AMR) AF: 0.0577 AC: 9 AN: 156

Ashkenazi Jewish (ASJ) AF: 0.0921 AC: 68 AN: 738

East Asian (EAS) AF: 0.0543 AC: 24 AN: 442

South Asian (SAS) AF: 0.0527 AC: 113 AN: 2144

European-Finnish (FIN) AF: 0.0714 AC: 3 AN: 42

Middle Eastern (MID) AF: 0.0882 AC: 21 AN: 238

European-Non Finnish (NFE) AF: 0.0714 AC: 6044 AN: 84650

Other (OTH) AF: 0.0726 AC: 247 AN: 3404

GnomAD4 genome AF: 0.00760 AC: 425 AN: 55906 Hom.: 1 Cov.: 0 AF XY: 0.00748 AC XY: 182 AN XY: 24326

African (AFR) AF: 0.0109 AC: 148 AN: 13600

American (AMR) AF: 0.00327 AC: 11 AN: 3360

Ashkenazi Jewish (ASJ) AF: 0.000505 AC: 1 AN: 1982

East Asian (EAS) AF: 0.0139 AC: 21 AN: 1508

South Asian (SAS) AF: 0.00 AC: 0 AN: 864

European-Finnish (FIN) AF: 0.00671 AC: 2 AN: 298

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 46

European-Non Finnish (NFE) AF: 0.00722 AC: 239 AN: 33110

Other (OTH) AF: 0.00315 AC: 2 AN: 634

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.31
Mutation Taster		=100/0	polymorphism

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: rs67417831; hg19: chr2-166150520;