NM_001349253.2:c.742C>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_001349253.2(SCN11A):c.742C>T(p.Arg248Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000446 in 1,613,914 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R248H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

SCN11A
NM_001349253.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 6.63

Publications

9 publications found

Variant links:

Genes affected

SCN11A (HGNC:10583): (sodium voltage-gated channel alpha subunit 11) Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with 24 transmembrane domains and one or more regulatory beta subunits. They are responsible for the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family, and is highly expressed in nociceptive neurons of dorsal root ganglia and trigeminal ganglia. It mediates brain-derived neurotrophic factor-evoked membrane depolarization and is a major effector of peripheral inflammatory pain hypersensitivity. Mutations in this gene have been associated with hereditary sensory and autonomic neuropathy type VII and familial episodic pain syndrome-3. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2017]

SCN11A Gene-Disease associations (from GenCC):

autosomal dominant hereditary sensory and autonomic neuropathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
familial episodic pain syndrome with predominantly lower limb involvement
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
hereditary sensory and autonomic neuropathy type 7
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
sodium channelopathy-related small fiber neuropathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SCN11A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0000472 (69/1461718) while in subpopulation EAS AF = 0.000252 (10/39698). AF 95% confidence interval is 0.000136. There are 0 homozygotes in GnomAdExome4. There are 28 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAdExome4 at 69 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001349253.2. 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
	SCN11A	NM_001349253.2	MANE Select	c.742C>T	p.Arg248Cys	missense	Exon 10 of 30	NP_001336182.1	Q9UI33-1
	SCN11A	NM_014139.3		c.742C>T	p.Arg248Cys	missense	Exon 6 of 26	NP_054858.2	Q9UI33-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SCN11A	ENST00000302328.9	TSL:5 MANE Select	c.742C>T	p.Arg248Cys	missense	Exon 10 of 30	ENSP00000307599.3	Q9UI33-1
SCN11A	ENST00000668754.1		c.742C>T	p.Arg248Cys	missense	Exon 13 of 33	ENSP00000499569.1	Q9UI33-1
SCN11A	ENST00000456224.7	TSL:5	c.742C>T	p.Arg248Cys	missense	Exon 6 of 25	ENSP00000416757.3	Q9UI33-3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000439

AC:

AN:

250620

AF XY:

0.0000517

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000619

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000472

AC:

AN:

1461718

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

727158

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000468

AC:

AN:

1111896

Other (OTH)

AF:

0.0000662

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

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

AF:

0.0000197

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41444

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68046

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.558

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:

0.000134

Hom.:

Bravo

AF:

0.0000340

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary sensory and autonomic neuropathy type 7;C3809899:Familial episodic pain syndrome with predominantly lower limb involvement (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Uncertain

0.066

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.88

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.45

MetaRNN

Uncertain

0.73

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.4

PhyloP100

6.6

PrimateAI

Benign

0.38

PROVEAN

Pathogenic

-4.6

REVEL

Pathogenic

0.84

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.028

Polyphen

1.0

Vest4

0.51

MVP

0.97

MPC

0.67

ClinPred

0.93

GERP RS

4.7

Varity_R

0.55

gMVP

0.66

Mutation Taster

=30/70

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over