Genetic Variant SCN9A:c.1975-4_1975-3dupTT (chr2-166281810-T-TAA) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_001365536.1(SCN9A):c.1975-4_1975-3dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000231 in 1,426,264 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00025 ( 1 hom. )

Consequence

SCN9A
NM_001365536.1 splice_region, intron

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.261

Publications

4 publications found

Variant links:

Genes affected

SCN9A (HGNC:10597): (sodium voltage-gated channel alpha subunit 9) This gene encodes a voltage-gated sodium channel which plays a significant role in nociception signaling. Mutations in this gene have been associated with primary erythermalgia, channelopathy-associated insensitivity to pain, and paroxysmal extreme pain disorder. [provided by RefSeq, Aug 2009]

SCN9A links:

SCN1A-AS1 (HGNC:54069): (SCN1A and SCN9A antisense RNA 1)

SCN1A-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP6

Variant 2-166281810-T-TAA is Benign according to our data. Variant chr2-166281810-T-TAA is described in ClinVar as Likely_benign. ClinVar VariationId is 696802.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1 link	c.1975-4_1975-3dupTT		splice_region_variant, intron_variant	Intron 12 of 26	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
SCN9A	ENST00000642356.2 link	c.1975-3_1975-2insTT	splice_region_variant, intron_variant	Intron 12 of 26		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11 link	c.1975-3_1975-2insTT	splice_region_variant, intron_variant	Intron 12 of 26	5		ENSP00000304748.7
SCN9A	ENST00000409672.5 link	c.1942-3_1942-2insTT	splice_region_variant, intron_variant	Intron 12 of 26	5		ENSP00000386306.1
SCN9A	ENST00000645907.1 link	c.1942-3_1942-2insTT	splice_region_variant, intron_variant	Intron 12 of 26			ENSP00000495983.1
SCN9A	ENST00000454569.6 link	c.1942-3_1942-2insTT	splice_region_variant, intron_variant	Intron 12 of 14	1		ENSP00000413212.2

Frequencies

GnomAD3 genomes

AF:

0.0000402

AC:

AN:

149284

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000246

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:

0.0000745

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000181

AC:

AN:

148910

AF XY:

0.000136

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000125

Gnomad ASJ exome

AF:

0.000585

Gnomad EAS exome

AF:

0.000101

Gnomad FIN exome

AF:

0.0000720

Gnomad NFE exome

AF:

0.000227

Gnomad OTH exome

AF:

0.000311

GnomAD4 exome

AF:

0.000254

AC:

324

AN:

1276980

Hom.:

Cov.:

AF XY:

0.000232

AC XY:

147

AN XY:

633768

show subpopulations

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

African (AFR)

AF:

0.000107

AC:

AN:

28156

American (AMR)

AF:

0.000175

AC:

AN:

34340

Ashkenazi Jewish (ASJ)

AF:

0.000413

AC:

AN:

21772

East Asian (EAS)

AF:

0.0000599

AC:

AN:

33372

South Asian (SAS)

AF:

0.000323

AC:

AN:

71144

European-Finnish (FIN)

AF:

0.000131

AC:

AN:

45900

Middle Eastern (MID)

AF:

0.00117

AC:

AN:

5136

European-Non Finnish (NFE)

AF:

0.000262

AC:

258

AN:

985236

Other (OTH)

AF:

0.000212

AC:

AN:

51924

⚠️ 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: 0.286

Heterozygous variant carriers

126

158

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

AF:

0.0000402

AC:

AN:

149284

Hom.:

Cov.:

AF XY:

0.0000412

AC XY:

AN XY:

72792

show subpopulations

African (AFR)

AF:

0.0000246

AC:

AN:

40722

American (AMR)

AF:

0.00

AC:

AN:

14918

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3436

East Asian (EAS)

AF:

0.00

AC:

AN:

5140

South Asian (SAS)

AF:

0.00

AC:

AN:

4716

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9940

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000745

AC:

AN:

67122

Other (OTH)

AF:

0.00

AC:

AN:

2068

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000625

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A

Benign:1

Nov 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.26

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over