19-35030823-G-C

Variant names:

• chr19-35030823-G-C
• rs2064208424
• NM_001037.5:c.3G>C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001037.5(SCN1B):​c.3G>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000067 in 149,324 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SCN1B NM_001037.5 start_lost
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 2.00
• Publications: 1 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 9 pathogenic variants. Next in-frame start position is after 34 codons. Genomic position: 35032587. Lost 0.152 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-35030823-G-C is Pathogenic according to our data. Variant chr19-35030823-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1040220.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001037.5. 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.3G>C	p.Met1?	start_lost	Exon 1 of 6	NP_001028.1	Q07699-1
	SCN1B	NM_199037.5		c.3G>C	p.Met1?	start_lost	Exon 1 of 3	NP_950238.1	Q07699-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1B	ENST00000262631.11	TSL:1 MANE Select	c.3G>C	p.Met1?	start_lost	Exon 1 of 6	ENSP00000262631.3	Q07699-1
	SCN1B	ENST00000415950.5	TSL:1	c.3G>C	p.Met1?	start_lost	Exon 1 of 3	ENSP00000396915.2	Q07699-2
	SCN1B	ENST00000638536.1	TSL:1	c.3G>C	p.Met1?	start_lost	Exon 1 of 5	ENSP00000492022.1	Q07699-1

Frequencies

GnomAD3 genomes AF: 0.00000670 AC: 1 AN: 149324 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000149

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 936554 Hom.: 0 Cov.: 13 AF XY: 0.00 AC XY: 0 AN XY: 457422

African (AFR) AF: 0.00 AC: 0 AN: 17416

American (AMR) AF: 0.00 AC: 0 AN: 7138

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10234

East Asian (EAS) AF: 0.00 AC: 0 AN: 13558

South Asian (SAS) AF: 0.00 AC: 0 AN: 40248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18206

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2300

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 793180

Other (OTH) AF: 0.00 AC: 0 AN: 34274

GnomAD4 genome AF: 0.00000670 AC: 1 AN: 149324 Hom.: 0 Cov.: 31 AF XY: 0.0000137 AC XY: 1 AN XY: 72812

African (AFR) AF: 0.00 AC: 0 AN: 41098

American (AMR) AF: 0.00 AC: 0 AN: 15066

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3416

East Asian (EAS) AF: 0.00 AC: 0 AN: 5092

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9642

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.0000149 AC: 1 AN: 66918

Other (OTH) AF: 0.00 AC: 0 AN: 2056

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	-	Brugada syndrome 5 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.23
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.50	D
PhyloP100		2.0
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.58
Sift	Benign	0.049	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0070	B
Vest4		0.38
MutPred		0.90		Gain of sheet (P = 0.0477)
MVP		0.93
ClinPred		0.88	D
GERP RS		2.3
PromoterAI		-0.085	Neutral
Varity_R		0.42
gMVP		0.86
Mutation Taster		=22/178	disease causing

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: rs2064208424; hg19: chr19-35521727;