2-165090495-G-A

Position:

• chr2-165090495-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_006922.4(SCN3A):​c.5658C>T​(p.Val1886=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.001 in 1,614,000 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (2 hom.)
• Consequence: SCN3A NM_006922.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.522

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 2-165090495-G-A is Benign according to our data. Variant chr2-165090495-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 412601.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165090495-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.522 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000657 (100/152234) while in subpopulation NFE AF= 0.00118 (80/68008). AF 95% confidence interval is 0.000968. There are 0 homozygotes in gnomad4. There are 47 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 100 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN3A	NM_006922.4	c.5658C>T	p.Val1886=	synonymous_variant	28/28	ENST00000283254.12	NP_008853.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN3A	ENST00000283254.12	c.5658C>T	p.Val1886=	synonymous_variant	28/28	1	NM_006922.4	ENSP00000283254	P1
	ENST00000638199.1	n.1144-625G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.000664 AC: 101 AN: 152116 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00119

Gnomad OTH AF: 0.000960

GnomAD3 exomes AF: 0.000832 AC: 209 AN: 251086 Hom.: 2 AF XY: 0.000870 AC XY: 118 AN XY: 135682

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00150

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.00104 AC: 1520 AN: 1461766 Hom.: 2 Cov.: 32 AF XY: 0.00105 AC XY: 761 AN XY: 727180

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00157

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000278

Gnomad4 FIN exome AF: 0.000524

Gnomad4 NFE exome AF: 0.00121

Gnomad4 OTH exome AF: 0.00118

GnomAD4 genome AF: 0.000657 AC: 100 AN: 152234 Hom.: 0 Cov.: 32 AF XY: 0.000631 AC XY: 47 AN XY: 74428

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00118

Gnomad4 OTH AF: 0.000950

Alfa AF: 0.000956 Hom.: 0

Bravo AF: 0.000518

EpiCase AF: 0.00142

EpiControl AF: 0.00142

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	SCN3A: BP4, BP7, BS1 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	5.5
DANN	Benign	0.86

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: rs141161490; hg19: chr2-165947005;