rs574777861

Positions:

• chr3-38921208-C-A
• chr3-38921208-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001349253.2(SCN11A):​c.760G>T​(p.Val254Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000769 in 1,614,050 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V254I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00044 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00080 (17 hom.)
• Consequence: SCN11A NM_001349253.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.82

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012769252).
• BP6: Variant 3-38921208-C-A is Benign according to our data. Variant chr3-38921208-C-A is described in ClinVar as [Benign]. Clinvar id is 474757.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00044 (67/152298) while in subpopulation SAS AF= 0.0137 (66/4828). AF 95% confidence interval is 0.011. There are 1 homozygotes in gnomad4. There are 52 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 67 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN11A	NM_001349253.2	c.760G>T	p.Val254Phe	missense_variant	10/30	ENST00000302328.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN11A	ENST00000302328.9	c.760G>T	p.Val254Phe	missense_variant	10/30	5	NM_001349253.2	A2

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152180 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0135

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00163 AC: 408 AN: 250888 Hom.: 4 AF XY: 0.00234 AC XY: 317 AN XY: 135570

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0129

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000803 AC: 1174 AN: 1461752 Hom.: 17 Cov.: 31 AF XY: 0.00120 AC XY: 872 AN XY: 727178

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0131

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.000596

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152298 Hom.: 1 Cov.: 32 AF XY: 0.000698 AC XY: 52 AN XY: 74474

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0137

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000670 Hom.: 0

Bravo AF: 0.0000907

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00183 AC: 222

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 04, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	18
DANN	Benign	0.92
DEOGEN2	Uncertain	0.58	D;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.034	N
LIST_S2	Uncertain	0.91	D;D;D
MetaRNN	Benign	0.013	T;T;T
MetaSVM	Uncertain	-0.064	T
MutationAssessor	Benign	1.2	L;L;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.2	N;N;N
REVEL	Uncertain	0.30
Sift	Benign	0.039	D;D;T
Sift4G	Benign	0.16	T;T;D
Polyphen		0.015	B;.;.
Vest4		0.52
MutPred		0.80		Gain of MoRF binding (P = 0.1193);Gain of MoRF binding (P = 0.1193);Gain of MoRF binding (P = 0.1193);
MVP		0.75
MPC		0.45
ClinPred		0.016	T
GERP RS		1.9
Varity_R		0.16
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs574777861; hg19: chr3-38962699;