rs72558028

Variant names:

• chr19-35034060-G-A
• rs72558028
• ENST00000415950.5:c.769G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-35034060-G-A
• chr19-35034060-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_199037.5(SCN1B):​c.769G>A​(p.Gly257Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00217 in 1,549,766 control chromosomes in the GnomAD database, including 4 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 Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. The gene SCN1B is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (3 hom.)
• Consequence: SCN1B NM_199037.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.295
• Publications: 15 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

Specifications for SCN1B are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004362136).
• BP6: Variant 19-35034060-G-A is Benign according to our data. Variant chr19-35034060-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 190850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0016 (243/152268) while in subpopulation NFE AF = 0.00231 (157/68006). AF 95% confidence interval is 0.00201. There are 1 homozygotes in GnomAd4. There are 119 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR,Unknown 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+321G>A		intron	N/A	NP_001028.1	Q07699-1
	SCN1B	NM_199037.5		c.769G>A	p.Gly257Arg	missense	Exon 3 of 3	NP_950238.1	Q07699-2
	SCN1B	NM_001321605.2		c.349+321G>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.769G>A	p.Gly257Arg	missense	Exon 3 of 3	ENSP00000396915.2	Q07699-2
	SCN1B	ENST00000262631.11	TSL:1 MANE Select	c.448+321G>A		intron	N/A	ENSP00000262631.3	Q07699-1
	SCN1B	ENST00000638536.1	TSL:1	c.448+321G>A		intron	N/A	ENSP00000492022.1	Q07699-1

Frequencies

GnomAD3 genomes AF: 0.00160 AC: 243 AN: 152150 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00231

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00143 AC: 221 AN: 154558 AF XY: 0.00157

Gnomad AFR exome AF: 0.000627

Gnomad AMR exome AF: 0.000567

Gnomad ASJ exome AF: 0.00305

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000851

Gnomad NFE exome AF: 0.00251

Gnomad OTH exome AF: 0.00138

GnomAD4 exome AF: 0.00223 AC: 3114 AN: 1397498 Hom.: 3 Cov.: 31 AF XY: 0.00222 AC XY: 1532 AN XY: 689372

African (AFR) AF: 0.000824 AC: 26 AN: 31560

American (AMR) AF: 0.000560 AC: 20 AN: 35700

Ashkenazi Jewish (ASJ) AF: 0.00362 AC: 91 AN: 25168

East Asian (EAS) AF: 0.00 AC: 0 AN: 35732

South Asian (SAS) AF: 0.000240 AC: 19 AN: 79200

European-Finnish (FIN) AF: 0.000730 AC: 36 AN: 49282

Middle Eastern (MID) AF: 0.00123 AC: 7 AN: 5694

European-Non Finnish (NFE) AF: 0.00259 AC: 2795 AN: 1077234

Other (OTH) AF: 0.00207 AC: 120 AN: 57928

GnomAD4 genome AF: 0.00160 AC: 243 AN: 152268 Hom.: 1 Cov.: 32 AF XY: 0.00160 AC XY: 119 AN XY: 74436

African (AFR) AF: 0.000842 AC: 35 AN: 41566

American (AMR) AF: 0.00157 AC: 24 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.000848 AC: 9 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00231 AC: 157 AN: 68006

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00232 Hom.: 1

Bravo AF: 0.00172

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000883 AC: 2

ESP6500EA AF: 0.00319 AC: 14

ExAC AF: 0.00102 AC: 37

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	3	not specified (3)
-	-	2	Brugada syndrome 5 (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Generalized epilepsy with febrile seizures plus, type 1;C2748541:Brugada syndrome 5;C3809311:Atrial fibrillation, familial, 13;C4479236:Developmental and epileptic encephalopathy, 52 (1)
-	-	1	SCN1B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	0.96
DANN	Benign	0.22
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0054	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-0.67	T
PhyloP100		-0.29
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.040	N
REVEL	Benign	0.16
Sift	Pathogenic	0.0	D
Polyphen		0.0010	B
Vest4		0.71
MutPred		0.33		Gain of MoRF binding (P = 0.0025)
MVP		0.27
MPC		0.80
ClinPred		0.0026	T
GERP RS		-2.0
gMVP		0.11
Mutation Taster		=97/3	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: rs72558028; hg19: chr19-35524964;