NM_006922.4:c.5889T>C

Variant names:

• chr2-165090264-A-G
• rs146624492
• NM_006922.4:c.5889T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_006922.4(SCN3A):​c.5889T>C​(p.Ser1963Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000417 in 1,612,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (0 hom.)
• Consequence: SCN3A NM_006922.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.223
• Publications: 1 publications found

Genes affected

SCN3A (HGNC:10590): (sodium voltage-gated channel alpha subunit 3) Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with 24 transmembrane domains and one or more regulatory beta subunits. They are responsible for the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family, and is found in a cluster of five alpha subunit genes on chromosome 2. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

SCN3A Gene-Disease associations (from GenCC):

• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Illumina, ClinGen, PanelApp Australia
• developmental and epileptic encephalopathy, 62

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• epilepsy, familial focal, with variable foci 4

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000236283 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 2-165090264-A-G is Benign according to our data. Variant chr2-165090264-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 288551.
• BP7: Synonymous conserved (PhyloP=0.223 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000315 (48/152172) while in subpopulation SAS AF = 0.000828 (4/4830). AF 95% confidence interval is 0.000392. There are 0 homozygotes in GnomAd4. There are 23 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 48 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006922.4. 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
	SCN3A	NM_006922.4	MANE Select	c.5889T>C	p.Ser1963Ser	synonymous	Exon 28 of 28	NP_008853.3
	SCN3A	NM_001081676.2		c.5742T>C	p.Ser1914Ser	synonymous	Exon 28 of 28	NP_001075145.1	Q9NY46-4
	SCN3A	NM_001081677.2		c.5742T>C	p.Ser1914Ser	synonymous	Exon 28 of 28	NP_001075146.1	Q9NY46-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN3A	ENST00000283254.12	TSL:1 MANE Select	c.5889T>C	p.Ser1963Ser	synonymous	Exon 28 of 28	ENSP00000283254.7	Q9NY46-3
	SCN3A	ENST00000409101.7	TSL:1	c.5742T>C	p.Ser1914Ser	synonymous	Exon 28 of 28	ENSP00000386726.3	Q9NY46-2
	SCN3A	ENST00000706067.1		c.5838T>C	p.Ser1946Ser	synonymous	Exon 28 of 28	ENSP00000516211.1	A0A994J5P2

Frequencies

GnomAD3 genomes AF: 0.000315 AC: 48 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000335 AC: 83 AN: 247782 AF XY: 0.000366

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.000401

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000745

Gnomad NFE exome AF: 0.000494

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000428 AC: 625 AN: 1459886 Hom.: 0 Cov.: 31 AF XY: 0.000460 AC XY: 334 AN XY: 726062

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.0000225 AC: 1 AN: 44506

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26066

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39672

South Asian (SAS) AF: 0.000209 AC: 18 AN: 85974

European-Finnish (FIN) AF: 0.000544 AC: 29 AN: 53298

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5762

European-Non Finnish (NFE) AF: 0.000493 AC: 548 AN: 1110830

Other (OTH) AF: 0.000232 AC: 14 AN: 60314

GnomAD4 genome AF: 0.000315 AC: 48 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74350

African (AFR) AF: 0.0000724 AC: 3 AN: 41434

American (AMR) AF: 0.0000655 AC: 1 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4830

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000529 AC: 36 AN: 68036

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.000383 Hom.: 0

Bravo AF: 0.000291

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	3.3
DANN	Benign	0.74
PhyloP100		0.22
Mutation Taster		=74/26	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: rs146624492; hg19: chr2-165946774;