19-35034040-G-C

Variant names:

• chr19-35034040-G-C
• rs67486287
• ENST00000415950.5:c.749G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000415950.5(SCN1B):​c.749G>C​(p.Arg250Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.142 in 1,549,996 control chromosomes in the GnomAD database, including 16,715 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R250K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.13 (1462 hom., cov: 32)
  • Exomes 𝑓: 0.14 (15253 hom.)
• Consequence: SCN1B ENST00000415950.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.409
• Publications: 31 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036869943).
• BP6: Variant 19-35034040-G-C is Benign according to our data. Variant chr19-35034040-G-C is described in ClinVar as Benign. ClinVar VariationId is 36756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.188 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000415950.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1B	NM_001037.5	MANE Select	c.448+301G>C		intron	N/A	NP_001028.1
	SCN1B	NM_199037.5		c.749G>C	p.Arg250Thr	missense	Exon 3 of 3	NP_950238.1
	SCN1B	NM_001321605.2		c.349+301G>C		intron	N/A	NP_001308534.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1B	ENST00000415950.5	TSL:1	c.749G>C	p.Arg250Thr	missense	Exon 3 of 3	ENSP00000396915.2
	SCN1B	ENST00000262631.11	TSL:1 MANE Select	c.448+301G>C		intron	N/A	ENSP00000262631.3
	SCN1B	ENST00000638536.1	TSL:1	c.448+301G>C		intron	N/A	ENSP00000492022.1

Frequencies

GnomAD3 genomes AF: 0.132 AC: 20133 AN: 151974 Hom.: 1465 Cov.: 32

Gnomad AFR AF: 0.0634

Gnomad AMI AF: 0.117

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.259

Gnomad EAS AF: 0.198

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.189

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.155

Gnomad OTH AF: 0.166

GnomAD2 exomes AF: 0.144 AC: 22249 AN: 154732 AF XY: 0.144

Gnomad AFR exome AF: 0.0617

Gnomad AMR exome AF: 0.0872

Gnomad ASJ exome AF: 0.256

Gnomad EAS exome AF: 0.213

Gnomad FIN exome AF: 0.183

Gnomad NFE exome AF: 0.152

Gnomad OTH exome AF: 0.156

GnomAD4 exome AF: 0.143 AC: 199879 AN: 1397904 Hom.: 15253 Cov.: 31 AF XY: 0.144 AC XY: 98954 AN XY: 689562

African (AFR) AF: 0.0596 AC: 1883 AN: 31572

American (AMR) AF: 0.0925 AC: 3303 AN: 35698

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 6627 AN: 25166

East Asian (EAS) AF: 0.195 AC: 6964 AN: 35732

South Asian (SAS) AF: 0.114 AC: 8996 AN: 79200

European-Finnish (FIN) AF: 0.180 AC: 8851 AN: 49262

Middle Eastern (MID) AF: 0.188 AC: 1072 AN: 5698

European-Non Finnish (NFE) AF: 0.142 AC: 153270 AN: 1077626

Other (OTH) AF: 0.154 AC: 8913 AN: 57950

GnomAD4 genome AF: 0.132 AC: 20122 AN: 152092 Hom.: 1462 Cov.: 32 AF XY: 0.134 AC XY: 9993 AN XY: 74340

African (AFR) AF: 0.0633 AC: 2629 AN: 41528

American (AMR) AF: 0.133 AC: 2027 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.259 AC: 896 AN: 3466

East Asian (EAS) AF: 0.198 AC: 1019 AN: 5154

South Asian (SAS) AF: 0.112 AC: 536 AN: 4786

European-Finnish (FIN) AF: 0.189 AC: 1997 AN: 10594

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.155 AC: 10509 AN: 67958

Other (OTH) AF: 0.164 AC: 347 AN: 2114

Alfa AF: 0.122 Hom.: 298

Bravo AF: 0.127

TwinsUK AF: 0.132 AC: 490

ALSPAC AF: 0.146 AC: 561

ESP6500AA AF: 0.0602 AC: 136

ESP6500EA AF: 0.145 AC: 639

ExAC AF: 0.0970 AC: 3853

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jul 22, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Jul 31, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 31% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 29. Only high quality variants are reported.

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Brugada syndrome 5 Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Cardiac arrhythmia Benign:1

Apr 22, 2013

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	11
DANN	Benign	0.93
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.096	N
LIST_S2	Benign	0.41	T
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.41
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.010	N
REVEL	Benign	0.047
Sift	Pathogenic	0.0	D
Polyphen		0.22	B
Vest4		0.096
MPC		1.4
ClinPred		0.013	T
GERP RS		1.8
gMVP		0.28
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs67486287; hg19: chr19-35524944; COSMIC: COSV52895059; COSMIC: COSV52895059;