Genetic Variant NM_001037.5:c.-40C>T (chr19-35030781-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001037.5(SCN1B):c.-40C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000279 in 717,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

SCN1B
NM_001037.5 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.967

Publications

0 publications found

Variant links:

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]

SCN1B links:

HPN-AS1 (HGNC:47041): (HPN antisense RNA 1)

HPN-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.38).

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SCN1B	NM_001037.5	MANE Select	c.-40C>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	NP_001028.1	Q07699-1
SCN1B	NM_001037.5	MANE Select	c.-40C>T	5_prime_UTR	Exon 1 of 6	NP_001028.1	Q07699-1
SCN1B	NM_199037.5		c.-40C>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 3	NP_950238.1	Q07699-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SCN1B	ENST00000262631.11	TSL:1 MANE Select	c.-40C>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	ENSP00000262631.3	Q07699-1
SCN1B	ENST00000415950.5	TSL:1	c.-40C>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 3	ENSP00000396915.2	Q07699-2
SCN1B	ENST00000638536.1	TSL:1	c.-40C>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	ENSP00000492022.1	Q07699-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000279

AC:

AN:

717920

Hom.:

Cov.:

AF XY:

0.00000274

AC XY:

AN XY:

364694

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

13600

American (AMR)

AF:

0.00

AC:

AN:

13428

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11532

East Asian (EAS)

AF:

0.00

AC:

AN:

11148

South Asian (SAS)

AF:

0.00

AC:

AN:

46354

European-Finnish (FIN)

AF:

0.00

AC:

AN:

18758

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2022

European-Non Finnish (NFE)

AF:

0.00000348

AC:

AN:

574062

Other (OTH)

AF:

0.00

AC:

AN:

27016

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

0.99

PhyloP100

0.97

PromoterAI

-0.068

Neutral

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over