chr19-35033920-T-C

Variant names:

• chr19-35033920-T-C
• rs55742440
• ENST00000415950.5:c.629T>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.629T>C​(p.Leu210Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.37 in 1,567,610 control chromosomes in the GnomAD database, including 110,048 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (13648 hom., cov: 32)
  • Exomes 𝑓: 0.37 (96400 hom.)
• Consequence: SCN1B ENST00000415950.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0130
• Publications: 41 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=8.393751E-5).
• BP6: Variant 19-35033920-T-C is Benign according to our data. Variant chr19-35033920-T-C is described in ClinVar as Benign. ClinVar VariationId is 138998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.517 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1B	NM_001037.5	c.448+181T>C		intron_variant	Intron 3 of 5	ENST00000262631.11	NP_001028.1
SCN1B	NM_199037.5	c.629T>C	p.Leu210Pro	missense_variant	Exon 3 of 3		NP_950238.1
SCN1B	NM_001321605.2	c.349+181T>C		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+181T>C		intron_variant	Intron 3 of 5	1	NM_001037.5	ENSP00000262631.3

Frequencies

GnomAD3 genomes AF: 0.417 AC: 63377 AN: 151816 Hom.: 13627 Cov.: 32

Gnomad AFR AF: 0.523

Gnomad AMI AF: 0.403

Gnomad AMR AF: 0.386

Gnomad ASJ AF: 0.506

Gnomad EAS AF: 0.258

Gnomad SAS AF: 0.299

Gnomad FIN AF: 0.404

Gnomad MID AF: 0.513

Gnomad NFE AF: 0.377

Gnomad OTH AF: 0.446

GnomAD2 exomes AF: 0.368 AC: 65107 AN: 176726 AF XY: 0.364

Gnomad AFR exome AF: 0.529

Gnomad AMR exome AF: 0.317

Gnomad ASJ exome AF: 0.494

Gnomad EAS exome AF: 0.268

Gnomad FIN exome AF: 0.404

Gnomad NFE exome AF: 0.384

Gnomad OTH exome AF: 0.403

GnomAD4 exome AF: 0.365 AC: 517037 AN: 1415674 Hom.: 96400 Cov.: 47 AF XY: 0.364 AC XY: 254721 AN XY: 700160

African (AFR) AF: 0.533 AC: 17159 AN: 32208

American (AMR) AF: 0.323 AC: 11902 AN: 36826

Ashkenazi Jewish (ASJ) AF: 0.499 AC: 12635 AN: 25344

East Asian (EAS) AF: 0.265 AC: 9733 AN: 36706

South Asian (SAS) AF: 0.293 AC: 23966 AN: 81744

European-Finnish (FIN) AF: 0.395 AC: 19935 AN: 50460

Middle Eastern (MID) AF: 0.510 AC: 2911 AN: 5708

European-Non Finnish (NFE) AF: 0.364 AC: 395992 AN: 1087988

Other (OTH) AF: 0.389 AC: 22804 AN: 58690

GnomAD4 genome AF: 0.418 AC: 63438 AN: 151936 Hom.: 13648 Cov.: 32 AF XY: 0.417 AC XY: 30958 AN XY: 74240

African (AFR) AF: 0.523 AC: 21671 AN: 41438

American (AMR) AF: 0.386 AC: 5892 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.506 AC: 1755 AN: 3466

East Asian (EAS) AF: 0.258 AC: 1323 AN: 5134

South Asian (SAS) AF: 0.299 AC: 1438 AN: 4810

European-Finnish (FIN) AF: 0.404 AC: 4271 AN: 10574

Middle Eastern (MID) AF: 0.514 AC: 150 AN: 292

European-Non Finnish (NFE) AF: 0.377 AC: 25629 AN: 67926

Other (OTH) AF: 0.446 AC: 942 AN: 2110

Alfa AF: 0.390 Hom.: 22232

Bravo AF: 0.421

TwinsUK AF: 0.360 AC: 1334

ALSPAC AF: 0.373 AC: 1438

ESP6500AA AF: 0.509 AC: 1290

ESP6500EA AF: 0.372 AC: 1675

ExAC AF: 0.327 AC: 35882

Asia WGS AF: 0.299 AC: 1039 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

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. -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

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

- -

Jul 15, 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 55% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 51. Only high quality variants are reported. -

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	Benign	0.043
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	5.5
DANN	Benign	0.60
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.00025	N
LIST_S2	Benign	0.14	T;T
MetaRNN	Benign	0.000084	T;T
MetaSVM	Benign	-0.98	T
PhyloP100		-0.013
PrimateAI	Benign	0.23	T
PROVEAN	Benign	1.8	N;.
REVEL	Benign	0.22
Sift	Pathogenic	0.0	D;.
Sift4G	Benign	0.062	T;.
Polyphen		0.0	B;.
Vest4		0.024
MPC		1.1
ClinPred		0.0078	T
GERP RS		-1.9
gMVP		0.11
Mutation Taster		=99/1	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: rs55742440; hg19: chr19-35524824; COSMIC: COSV52895038; COSMIC: COSV52895038;