chr19-35039169-T-C

Variant names:

• chr19-35039169-T-C
• rs16969930
• NM_001037.5:c.501T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001037.5(SCN1B):​c.501T>C​(p.Ile167Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0283 in 1,614,122 control chromosomes in the GnomAD database, including 756 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (49 hom., cov: 32)
  • Exomes 𝑓: 0.029 (707 hom.)
• Consequence: SCN1B NM_001037.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.00200
• Publications: 8 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 19-35039169-T-C is Benign according to our data. Variant chr19-35039169-T-C is described in ClinVar as Benign. ClinVar VariationId is 130210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.002 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0198 (3014/152282) while in subpopulation SAS AF = 0.0338 (163/4824). AF 95% confidence interval is 0.0297. There are 49 homozygotes in GnomAd4. There are 1370 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 49 AD,Unknown,AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1B	NM_001037.5	MANE Select	c.501T>C	p.Ile167Ile	synonymous	Exon 4 of 6	NP_001028.1
	SCN1B	NM_001321605.2		c.402T>C	p.Ile134Ile	synonymous	Exon 4 of 6	NP_001308534.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1B	ENST00000262631.11	TSL:1 MANE Select	c.501T>C	p.Ile167Ile	synonymous	Exon 4 of 6	ENSP00000262631.3
	SCN1B	ENST00000638536.1	TSL:1	c.501T>C	p.Ile167Ile	synonymous	Exon 4 of 5	ENSP00000492022.1
	SCN1B	ENST00000675741.1		c.528T>C	p.Ile176Ile	synonymous	Exon 4 of 6	ENSP00000502395.1

Frequencies

GnomAD3 genomes AF: 0.0198 AC: 3013 AN: 152164 Hom.: 50 Cov.: 32

Gnomad AFR AF: 0.00594

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0120

Gnomad ASJ AF: 0.0349

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0340

Gnomad FIN AF: 0.0140

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0308

Gnomad OTH AF: 0.0153

GnomAD2 exomes AF: 0.0231 AC: 5811 AN: 251484 AF XY: 0.0248

Gnomad AFR exome AF: 0.00652

Gnomad AMR exome AF: 0.00919

Gnomad ASJ exome AF: 0.0319

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0128

Gnomad NFE exome AF: 0.0316

Gnomad OTH exome AF: 0.0238

GnomAD4 exome AF: 0.0292 AC: 42669 AN: 1461840 Hom.: 707 Cov.: 31 AF XY: 0.0294 AC XY: 21368 AN XY: 727234

African (AFR) AF: 0.00517 AC: 173 AN: 33480

American (AMR) AF: 0.0100 AC: 448 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0307 AC: 803 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0337 AC: 2904 AN: 86258

European-Finnish (FIN) AF: 0.0130 AC: 692 AN: 53414

Middle Eastern (MID) AF: 0.0286 AC: 165 AN: 5768

European-Non Finnish (NFE) AF: 0.0324 AC: 35985 AN: 1111966

Other (OTH) AF: 0.0248 AC: 1497 AN: 60396

GnomAD4 genome AF: 0.0198 AC: 3014 AN: 152282 Hom.: 49 Cov.: 32 AF XY: 0.0184 AC XY: 1370 AN XY: 74458

African (AFR) AF: 0.00592 AC: 246 AN: 41568

American (AMR) AF: 0.0120 AC: 183 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0349 AC: 121 AN: 3468

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5174

South Asian (SAS) AF: 0.0338 AC: 163 AN: 4824

European-Finnish (FIN) AF: 0.0140 AC: 149 AN: 10618

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0308 AC: 2098 AN: 68010

Other (OTH) AF: 0.0151 AC: 32 AN: 2114

Alfa AF: 0.0275 Hom.: 107

Bravo AF: 0.0183

Asia WGS AF: 0.0120 AC: 43 AN: 3478

EpiCase AF: 0.0322

EpiControl AF: 0.0321

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Brugada syndrome 5 (2)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Generalized epilepsy with febrile seizures plus, type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	6.0
DANN	Benign	0.73
PhyloP100		0.0020
Mutation Taster		=100/0	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: rs16969930; hg19: chr19-35530073; COSMIC: COSV105008355; COSMIC: COSV105008355;