rs150835546

Variant names:

• chr3-38950268-G-A
• rs150835546
• NM_001349253.2:c.95C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-38950268-G-A
• chr3-38950268-G-C
• chr3-38950268-G-T

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.95C>T​(p.Ala32Val) variant causes a missense change. The variant allele was found at a frequency of 0.000833 in 1,613,978 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. A32P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00086 (0 hom.)
• Consequence: SCN11A NM_001349253.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:2 B:5
• Conservation: PhyloP100: 5.61
• Publications: 7 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=0.03544855).
• BP6: Variant 3-38950268-G-A is Benign according to our data. Variant chr3-38950268-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 474759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000552 (84/152140) while in subpopulation NFE AF = 0.000941 (64/68018). AF 95% confidence interval is 0.000755. There are 0 homozygotes in GnomAd4. There are 36 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 84 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.95C>T	p.Ala32Val	missense	Exon 5 of 30	NP_001336182.1	Q9UI33-1
	SCN11A	NM_014139.3		c.95C>T	p.Ala32Val	missense	Exon 1 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.95C>T	p.Ala32Val	missense	Exon 5 of 30	ENSP00000307599.3	Q9UI33-1
	SCN11A	ENST00000668754.1		c.95C>T	p.Ala32Val	missense	Exon 8 of 33	ENSP00000499569.1	Q9UI33-1
	SCN11A	ENST00000456224.7	TSL:5	c.95C>T	p.Ala32Val	missense	Exon 1 of 25	ENSP00000416757.3	Q9UI33-3

Frequencies

GnomAD3 genomes AF: 0.000553 AC: 84 AN: 152022 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000756

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000941

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000652 AC: 164 AN: 251478 AF XY: 0.000670

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00105

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000862 AC: 1260 AN: 1461838 Hom.: 0 Cov.: 33 AF XY: 0.000901 AC XY: 655 AN XY: 727214

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.000470 AC: 21 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00142 AC: 37 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86256

European-Finnish (FIN) AF: 0.000712 AC: 38 AN: 53400

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5762

European-Non Finnish (NFE) AF: 0.00101 AC: 1121 AN: 1111990

Other (OTH) AF: 0.000530 AC: 32 AN: 60392

GnomAD4 genome AF: 0.000552 AC: 84 AN: 152140 Hom.: 0 Cov.: 31 AF XY: 0.000484 AC XY: 36 AN XY: 74368

African (AFR) AF: 0.0000723 AC: 3 AN: 41482

American (AMR) AF: 0.000458 AC: 7 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.000756 AC: 8 AN: 10588

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

European-Non Finnish (NFE) AF: 0.000941 AC: 64 AN: 68018

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000901 Hom.: 0

Bravo AF: 0.000555

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000634 AC: 77

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.00101

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	2	not provided (4)
-	-	1	Hereditary sensory and autonomic neuropathy type 7;C3809899:Familial episodic pain syndrome with predominantly lower limb involvement (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	SCN11A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	-0.055
Eigen_PC	Benign	-0.050
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.035	T
MetaSVM	Uncertain	0.31	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		5.6
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.30
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.025	D
Polyphen		0.41	B
Vest4		0.27
MVP		0.95
MPC		0.19
ClinPred		0.057	T
GERP RS		2.1
PromoterAI		0.016	Neutral
Varity_R		0.069
gMVP		0.42
Mutation Taster		=82/18	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: rs150835546; hg19: chr3-38991759;