rs1275085

Positions:

• chr11-123642453-G-A
• chr11-123642453-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The ENST00000299333.8(SCN3B):​c.438C>T​(p.Thr146=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0859 in 1,613,836 control chromosomes in the GnomAD database, including 6,568 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T146T) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.088 (648 hom., cov: 32)
  • Exomes 𝑓: 0.086 (5920 hom.)
• Consequence: SCN3B ENST00000299333.8 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.06

Genes affected

SCN3B (HGNC:20665): (sodium voltage-gated channel beta subunit 3) Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit 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 beta subunit gene family, and influences the inactivation kinetics of the sodium channel. Two alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 11-123642453-G-A is Benign according to our data. Variant chr11-123642453-G-A is described in ClinVar as [Benign]. Clinvar id is 261028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-123642453-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.07 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN3B	NM_001040151.2	c.438C>T	p.Thr146=	synonymous_variant	4/7	ENST00000299333.8	NP_001035241.1
SCN3B	NM_018400.4	c.438C>T	p.Thr146=	synonymous_variant	3/6		NP_060870.1
SCN3B	XM_011542897.3	c.438C>T	p.Thr146=	synonymous_variant	4/7		XP_011541199.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN3B	ENST00000299333.8	c.438C>T	p.Thr146=	synonymous_variant	4/7	1	NM_001040151.2	ENSP00000299333	P1

Frequencies

GnomAD3 genomes AF: 0.0882 AC: 13401 AN: 152002 Hom.: 647 Cov.: 32

Gnomad AFR AF: 0.0962

Gnomad AMI AF: 0.145

Gnomad AMR AF: 0.0540

Gnomad ASJ AF: 0.140

Gnomad EAS AF: 0.00290

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.0951

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.0877

Gnomad OTH AF: 0.0904

GnomAD3 exomes AF: 0.0864 AC: 21697 AN: 251046 Hom.: 1168 AF XY: 0.0920 AC XY: 12483 AN XY: 135724

Gnomad AFR exome AF: 0.0967

Gnomad AMR exome AF: 0.0380

Gnomad ASJ exome AF: 0.133

Gnomad EAS exome AF: 0.00261

Gnomad SAS exome AF: 0.158

Gnomad FIN exome AF: 0.0930

Gnomad NFE exome AF: 0.0881

Gnomad OTH exome AF: 0.0944

GnomAD4 exome AF: 0.0856 AC: 125191 AN: 1461716 Hom.: 5920 Cov.: 33 AF XY: 0.0883 AC XY: 64235 AN XY: 727182

Gnomad4 AFR exome AF: 0.0956

Gnomad4 AMR exome AF: 0.0410

Gnomad4 ASJ exome AF: 0.134

Gnomad4 EAS exome AF: 0.00181

Gnomad4 SAS exome AF: 0.157

Gnomad4 FIN exome AF: 0.0916

Gnomad4 NFE exome AF: 0.0830

Gnomad4 OTH exome AF: 0.0862

GnomAD4 genome AF: 0.0881 AC: 13401 AN: 152120 Hom.: 648 Cov.: 32 AF XY: 0.0892 AC XY: 6635 AN XY: 74372

Gnomad4 AFR AF: 0.0960

Gnomad4 AMR AF: 0.0539

Gnomad4 ASJ AF: 0.140

Gnomad4 EAS AF: 0.00291

Gnomad4 SAS AF: 0.157

Gnomad4 FIN AF: 0.0951

Gnomad4 NFE AF: 0.0878

Gnomad4 OTH AF: 0.0890

Alfa AF: 0.0860 Hom.: 1022

Bravo AF: 0.0835

Asia WGS AF: 0.0610 AC: 214 AN: 3478

EpiCase AF: 0.0932

EpiControl AF: 0.0925

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 09, 2023	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 23, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Brugada syndrome 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	5.9
DANN	Benign	0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1275085; hg19: chr11-123513161;