rs138034948

Variant names:

• chr3-38909187-C-T
• rs138034948
• NM_001349253.2:c.1109G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-38909187-C-T
• chr3-38909187-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001349253.2(SCN11A):​c.1109G>A​(p.Arg370His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000283 in 1,613,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R370G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: SCN11A NM_001349253.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.34
• Publications: 10 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.018566787).
• BP6: Variant 3-38909187-C-T is Benign according to our data. Variant chr3-38909187-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 541603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00127 (193/152302) while in subpopulation AFR AF = 0.00438 (182/41564). AF 95% confidence interval is 0.00386. There are 0 homozygotes in GnomAd4. There are 88 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 193 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.1109G>A	p.Arg370His	missense	Exon 13 of 30	NP_001336182.1	Q9UI33-1
	SCN11A	NM_014139.3		c.1109G>A	p.Arg370His	missense	Exon 9 of 26	NP_054858.2	Q9UI33-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN11A	ENST00000302328.9	TSL:5 MANE Select	c.1109G>A	p.Arg370His	missense	Exon 13 of 30	ENSP00000307599.3	Q9UI33-1
	SCN11A	ENST00000668754.1		c.1109G>A	p.Arg370His	missense	Exon 16 of 33	ENSP00000499569.1	Q9UI33-1
	SCN11A	ENST00000456224.7	TSL:5	c.1109G>A	p.Arg370His	missense	Exon 9 of 25	ENSP00000416757.3	Q9UI33-3

Frequencies

GnomAD3 genomes AF: 0.00126 AC: 191 AN: 152184 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000327 AC: 82 AN: 250990 AF XY: 0.000206

Gnomad AFR exome AF: 0.00406

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000970

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000180 AC: 263 AN: 1461642 Hom.: 0 Cov.: 32 AF XY: 0.000172 AC XY: 125 AN XY: 727122

African (AFR) AF: 0.00293 AC: 98 AN: 33468

American (AMR) AF: 0.000179 AC: 8 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5762

European-Non Finnish (NFE) AF: 0.000117 AC: 130 AN: 1111846

Other (OTH) AF: 0.000331 AC: 20 AN: 60382

GnomAD4 genome AF: 0.00127 AC: 193 AN: 152302 Hom.: 0 Cov.: 31 AF XY: 0.00118 AC XY: 88 AN XY: 74472

African (AFR) AF: 0.00438 AC: 182 AN: 41564

American (AMR) AF: 0.000131 AC: 2 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68028

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000443 Hom.: 0

Bravo AF: 0.00115

ESP6500AA AF: 0.00499 AC: 22

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000453 AC: 55

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hereditary sensory and autonomic neuropathy type 7;C3809899:Familial episodic pain syndrome with predominantly lower limb involvement (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.90	D
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.28	N
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.019	T
MetaSVM	Uncertain	0.64	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		1.3
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.057	T
Polyphen		0.30	B
Vest4		0.34
MVP		0.90
MPC		0.19
ClinPred		0.074	T
GERP RS		0.86
Varity_R		0.16
gMVP		0.81
Mutation Taster		=76/24	polymorphism

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: rs138034948; hg19: chr3-38950678; COSMIC: COSV56566581;