chr19-35030832-G-A

Variant names:

• chr19-35030832-G-A
• NM_001037.5:c.12G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_001037.5(SCN1B):​c.12G>A​(p.Leu4Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000033 in 908,762 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 Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000033 (0 hom.)
• Consequence: SCN1B NM_001037.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.30
• Publications: 0 publications found

Genes affected

SCN1B (HGNC:10586): (sodium voltage-gated channel beta subunit 1) Voltage-gated sodium channels are heteromeric proteins that function in the generation and propagation of action potentials in muscle and neuronal cells. They are composed of one alpha and two beta subunits, where the alpha subunit provides channel activity and the beta-1 subunit modulates the kinetics of channel inactivation. This gene encodes a sodium channel beta-1 subunit. Mutations in this gene result in generalized epilepsy with febrile seizures plus, Brugada syndrome 5, and defects in cardiac conduction. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Oct 2009]

HPN-AS1 (HGNC:47041): (HPN antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 19-35030832-G-A is Benign according to our data. Variant chr19-35030832-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1769364.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.3 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1B	NM_001037.5	c.12G>A	p.Leu4Leu	synonymous_variant	Exon 1 of 6	ENST00000262631.11	NP_001028.1
SCN1B	NM_199037.5	c.12G>A	p.Leu4Leu	synonymous_variant	Exon 1 of 3		NP_950238.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1B	ENST00000262631.11	c.12G>A	p.Leu4Leu	synonymous_variant	Exon 1 of 6	1	NM_001037.5	ENSP00000262631.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000330 AC: 3 AN: 908762 Hom.: 0 Cov.: 13 AF XY: 0.00000454 AC XY: 2 AN XY: 440368

⚠️ 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: 16988

American (AMR) AF: 0.00 AC: 0 AN: 5752

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9418

East Asian (EAS) AF: 0.00 AC: 0 AN: 13298

South Asian (SAS) AF: 0.0000296 AC: 1 AN: 33748

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 16808

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2252

European-Non Finnish (NFE) AF: 0.00000257 AC: 2 AN: 777336

Other (OTH) AF: 0.00 AC: 0 AN: 33162

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Benign:1

Aug 30, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	12
DANN	Benign	0.97
PhyloP100		1.3
PromoterAI		-0.095	Neutral
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

hg19: chr19-35521736;