rs66876876

Variant names:

• chr19-35033932-G-A
• rs66876876
• ENST00000415950.5:c.641G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_199037.5(SCN1B):​c.641G>A​(p.Arg214Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00306 in 1,559,664 control chromosomes in the GnomAD database, including 9 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R214W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (8 hom.)
• Consequence: SCN1B NM_199037.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:12 O:1
• Conservation: PhyloP100: -0.828
• Publications: 32 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005021572).
• BP6: Variant 19-35033932-G-A is Benign according to our data. Variant chr19-35033932-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 190847.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00219 (334/152296) while in subpopulation NFE AF = 0.00382 (260/68026). AF 95% confidence interval is 0.00344. There are 1 homozygotes in GnomAd4. There are 149 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 8 AD,Unknown,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_199037.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1B	NM_001037.5	MANE Select	c.448+193G>A		intron	N/A	NP_001028.1	Q07699-1
	SCN1B	NM_199037.5		c.641G>A	p.Arg214Gln	missense	Exon 3 of 3	NP_950238.1	Q07699-2
	SCN1B	NM_001321605.2		c.349+193G>A		intron	N/A	NP_001308534.1	A0A1W2PR05

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1B	ENST00000415950.5	TSL:1	c.641G>A	p.Arg214Gln	missense	Exon 3 of 3	ENSP00000396915.2	Q07699-2
	SCN1B	ENST00000262631.11	TSL:1 MANE Select	c.448+193G>A		intron	N/A	ENSP00000262631.3	Q07699-1
	SCN1B	ENST00000638536.1	TSL:1	c.448+193G>A		intron	N/A	ENSP00000492022.1	Q07699-1

Frequencies

GnomAD3 genomes AF: 0.00219 AC: 334 AN: 152178 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00264

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00382

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00236 AC: 388 AN: 164114 AF XY: 0.00234

Gnomad AFR exome AF: 0.000458

Gnomad AMR exome AF: 0.000597

Gnomad ASJ exome AF: 0.000231

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00413

Gnomad NFE exome AF: 0.00423

Gnomad OTH exome AF: 0.00306

GnomAD4 exome AF: 0.00315 AC: 4437 AN: 1407368 Hom.: 8 Cov.: 33 AF XY: 0.00301 AC XY: 2091 AN XY: 695134

African (AFR) AF: 0.000470 AC: 15 AN: 31882

American (AMR) AF: 0.000554 AC: 20 AN: 36126

Ashkenazi Jewish (ASJ) AF: 0.000435 AC: 11 AN: 25262

East Asian (EAS) AF: 0.00 AC: 0 AN: 36118

South Asian (SAS) AF: 0.000521 AC: 42 AN: 80662

European-Finnish (FIN) AF: 0.00359 AC: 179 AN: 49914

Middle Eastern (MID) AF: 0.00193 AC: 11 AN: 5700

European-Non Finnish (NFE) AF: 0.00371 AC: 4015 AN: 1083326

Other (OTH) AF: 0.00247 AC: 144 AN: 58378

GnomAD4 genome AF: 0.00219 AC: 334 AN: 152296 Hom.: 1 Cov.: 32 AF XY: 0.00200 AC XY: 149 AN XY: 74478

African (AFR) AF: 0.000602 AC: 25 AN: 41562

American (AMR) AF: 0.000588 AC: 9 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00264 AC: 28 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00382 AC: 260 AN: 68026

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00294 Hom.: 0

Bravo AF: 0.00222

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000806 AC: 2

ESP6500EA AF: 0.00469 AC: 21

ExAC AF: 0.00250 AC: 270

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	6	not provided (9)
-	1	5	not specified (6)
-	1	1	Brugada syndrome 5 (2)
-	1	-	Atrial fibrillation, familial, 13 (1)
-	1	-	Developmental and epileptic encephalopathy, 52 (1)
-	1	-	Generalized epilepsy with febrile seizures plus, type 1 (1)
-	1	-	Long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	1.3
DANN	Benign	0.97
Eigen	Benign	-0.95
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.0050	T
MetaSVM	Benign	-0.73	T
PhyloP100		-0.83
PrimateAI	Benign	0.17	T
PROVEAN	Benign	0.31	N
REVEL	Benign	0.062
Sift	Benign	0.34	T
Polyphen		0.017	B
Vest4		0.14
MVP		0.79
MPC		0.84
ClinPred		0.0019	T
GERP RS		0.78
gMVP		0.13
Mutation Taster		=94/6	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

dbSNP: rs66876876; hg19: chr19-35524836; COSMIC: COSV99386640; COSMIC: COSV99386640;