rs67701503

Variant names:

• chr19-35034035-C-A
• rs67701503
• ENST00000415950.5:c.744C>A

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.744C>A​(p.Ser248Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.144 in 1,549,658 control chromosomes in the GnomAD database, including 16,941 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S248I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.14 (1552 hom., cov: 31)
  • Exomes 𝑓: 0.14 (15389 hom.)
• Consequence: SCN1B ENST00000415950.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.294
• Publications: 27 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=0.001129061).
• BP6: Variant 19-35034035-C-A is Benign according to our data. Variant chr19-35034035-C-A is described in ClinVar as Benign. ClinVar VariationId is 138999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.187 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1B	NM_001037.5	c.448+296C>A		intron_variant	Intron 3 of 5	ENST00000262631.11	NP_001028.1
SCN1B	NM_199037.5	c.744C>A	p.Ser248Arg	missense_variant	Exon 3 of 3		NP_950238.1
SCN1B	NM_001321605.2	c.349+296C>A		intron_variant	Intron 3 of 5		NP_001308534.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1B	ENST00000262631.11	c.448+296C>A		intron_variant	Intron 3 of 5	1	NM_001037.5	ENSP00000262631.3

Frequencies

GnomAD3 genomes AF: 0.140 AC: 21339 AN: 151926 Hom.: 1555 Cov.: 31

Gnomad AFR AF: 0.0910

Gnomad AMI AF: 0.117

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.259

Gnomad EAS AF: 0.197

Gnomad SAS AF: 0.116

Gnomad FIN AF: 0.189

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.155

Gnomad OTH AF: 0.170

GnomAD2 exomes AF: 0.146 AC: 22627 AN: 154816 AF XY: 0.147

Gnomad AFR exome AF: 0.0891

Gnomad AMR exome AF: 0.0884

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: 0.144 AC: 201504 AN: 1397614 Hom.: 15389 Cov.: 31 AF XY: 0.145 AC XY: 99781 AN XY: 689434

African (AFR) AF: 0.0899 AC: 2839 AN: 31566

American (AMR) AF: 0.0939 AC: 3354 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 6630 AN: 25172

East Asian (EAS) AF: 0.195 AC: 6964 AN: 35726

South Asian (SAS) AF: 0.119 AC: 9390 AN: 79206

European-Finnish (FIN) AF: 0.180 AC: 8873 AN: 49274

Middle Eastern (MID) AF: 0.191 AC: 1086 AN: 5698

European-Non Finnish (NFE) AF: 0.142 AC: 153335 AN: 1077332

Other (OTH) AF: 0.156 AC: 9033 AN: 57936

GnomAD4 genome AF: 0.140 AC: 21333 AN: 152044 Hom.: 1552 Cov.: 31 AF XY: 0.142 AC XY: 10543 AN XY: 74318

African (AFR) AF: 0.0910 AC: 3773 AN: 41484

American (AMR) AF: 0.135 AC: 2055 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.259 AC: 897 AN: 3466

East Asian (EAS) AF: 0.197 AC: 1014 AN: 5158

South Asian (SAS) AF: 0.116 AC: 553 AN: 4784

European-Finnish (FIN) AF: 0.189 AC: 2001 AN: 10600

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

European-Non Finnish (NFE) AF: 0.155 AC: 10521 AN: 67956

Other (OTH) AF: 0.169 AC: 357 AN: 2116

Alfa AF: 0.154 Hom.: 4171

Bravo AF: 0.136

TwinsUK AF: 0.132 AC: 488

ALSPAC AF: 0.146 AC: 562

ESP6500AA AF: 0.0844 AC: 190

ESP6500EA AF: 0.146 AC: 640

ExAC AF: 0.0943 AC: 3981

Asia WGS AF: 0.116 AC: 401 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

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 32% 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: 30. Only high quality variants are reported. -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

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. -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	13
DANN	Uncertain	0.99
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.42	T;T
MetaRNN	Benign	0.0011	T;T
MetaSVM	Benign	-0.99	T
PhyloP100		0.29
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.040	N;.
REVEL	Benign	0.11
Sift	Pathogenic	0.0	D;.
Polyphen		0.0020	B;.
Vest4		0.11
MutPred		0.26		Gain of sheet (P = 0.0149);.;
MPC		1.3
ClinPred		0.039	T
GERP RS		1.9
gMVP		0.24
Mutation Taster		=98/2	polymorphism (auto)

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: rs67701503; hg19: chr19-35524939; COSMIC: COSV52895048; COSMIC: COSV52895048;