rs767279633

Variant names:

• chr3-38896864-G-A
• rs767279633
• NM_001349253.2:c.2384C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001349253.2(SCN11A):​c.2384C>T​(p.Thr795Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000154 in 1,556,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T795T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000042 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: SCN11A NM_001349253.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 7.48
• Publications: 3 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.053943515).
• BP6: Variant 3-38896864-G-A is Benign according to our data. Variant chr3-38896864-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 474706.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000127 (18/1412376) while in subpopulation AMR AF = 0.0000981 (4/40774). AF 95% confidence interval is 0.0000329. There are 0 homozygotes in GnomAdExome4. There are 10 alleles in the male GnomAdExome4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 6 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.2384C>T	p.Thr795Met	missense	Exon 18 of 30	NP_001336182.1	Q9UI33-1
	SCN11A	NM_014139.3		c.2384C>T	p.Thr795Met	missense	Exon 14 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.2384C>T	p.Thr795Met	missense	Exon 18 of 30	ENSP00000307599.3	Q9UI33-1
	SCN11A	ENST00000668754.1		c.2384C>T	p.Thr795Met	missense	Exon 21 of 33	ENSP00000499569.1	Q9UI33-1
	SCN11A	ENST00000456224.7	TSL:5	c.2384C>T	p.Thr795Met	missense	Exon 14 of 25	ENSP00000416757.3	Q9UI33-3

Frequencies

GnomAD3 genomes AF: 0.0000418 AC: 6 AN: 143584 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000522

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: 0.0000596

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000385 AC: 9 AN: 233696 AF XY: 0.0000396

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000650

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000651

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000127 AC: 18 AN: 1412376 Hom.: 0 Cov.: 34 AF XY: 0.0000144 AC XY: 10 AN XY: 696274

African (AFR) AF: 0.00 AC: 0 AN: 32122

American (AMR) AF: 0.0000981 AC: 4 AN: 40774

Ashkenazi Jewish (ASJ) AF: 0.0000806 AC: 2 AN: 24808

East Asian (EAS) AF: 0.0000263 AC: 1 AN: 38034

South Asian (SAS) AF: 0.00 AC: 0 AN: 79302

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5480

European-Non Finnish (NFE) AF: 0.0000102 AC: 11 AN: 1081306

Other (OTH) AF: 0.00 AC: 0 AN: 58166

GnomAD4 genome AF: 0.0000418 AC: 6 AN: 143672 Hom.: 0 Cov.: 30 AF XY: 0.0000290 AC XY: 2 AN XY: 68886

African (AFR) AF: 0.0000521 AC: 2 AN: 38422

American (AMR) AF: 0.00 AC: 0 AN: 13836

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3448

East Asian (EAS) AF: 0.00 AC: 0 AN: 4910

South Asian (SAS) AF: 0.00 AC: 0 AN: 4600

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8206

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 274

European-Non Finnish (NFE) AF: 0.0000596 AC: 4 AN: 67092

Other (OTH) AF: 0.00 AC: 0 AN: 1980

Alfa AF: 0.0000959 Hom.: 0

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	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	0.076
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	16
DANN	Benign	0.097
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.15	N
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.054	T
MetaSVM	Uncertain	0.055	D
MutationAssessor	Benign	-1.8	N
PhyloP100		7.5
PrimateAI	Benign	0.32	T
PROVEAN	Benign	4.7	N
REVEL	Uncertain	0.38
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.017	B
Vest4		0.16
MutPred		0.54		Loss of catalytic residue at T795 (P = 0.064)
MVP		0.77
MPC		0.15
ClinPred		0.047	T
GERP RS		4.8
Varity_R		0.044
gMVP		0.13
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs767279633; hg19: chr3-38938355; COSMIC: COSV104536874;