rs72869687

Positions:

• chr3-38847244-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001349253.2(SCN11A):​c.4826C>T​(p.Thr1609Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0223 in 1,614,022 control chromosomes in the GnomAD database, including 1,082 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (225 hom., cov: 32)
  • Exomes 𝑓: 0.021 (857 hom.)
• Consequence: SCN11A NM_001349253.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.57

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.4528327E-4).
• BP6: Variant 3-38847244-G-A is Benign according to our data. Variant chr3-38847244-G-A is described in ClinVar as [Benign]. Clinvar id is 474735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38847244-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN11A	NM_001349253.2	c.4826C>T	p.Thr1609Ile	missense_variant	30/30	ENST00000302328.9	NP_001336182.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN11A	ENST00000302328.9	c.4826C>T	p.Thr1609Ile	missense_variant	30/30	5	NM_001349253.2	ENSP00000307599	A2

Frequencies

GnomAD3 genomes AF: 0.0389 AC: 5917 AN: 152196 Hom.: 227 Cov.: 32

Gnomad AFR AF: 0.0789

Gnomad AMI AF: 0.0877

Gnomad AMR AF: 0.0284

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.165

Gnomad SAS AF: 0.0429

Gnomad FIN AF: 0.00922

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0127

Gnomad OTH AF: 0.0292

GnomAD3 exomes AF: 0.0371 AC: 9321 AN: 250904 Hom.: 425 AF XY: 0.0339 AC XY: 4600 AN XY: 135572

Gnomad AFR exome AF: 0.0796

Gnomad AMR exome AF: 0.0557

Gnomad ASJ exome AF: 0.0105

Gnomad EAS exome AF: 0.163

Gnomad SAS exome AF: 0.0369

Gnomad FIN exome AF: 0.00782

Gnomad NFE exome AF: 0.0137

Gnomad OTH exome AF: 0.0245

GnomAD4 exome AF: 0.0205 AC: 30020 AN: 1461708 Hom.: 857 Cov.: 33 AF XY: 0.0205 AC XY: 14907 AN XY: 727148

Gnomad4 AFR exome AF: 0.0776

Gnomad4 AMR exome AF: 0.0510

Gnomad4 ASJ exome AF: 0.0103

Gnomad4 EAS exome AF: 0.147

Gnomad4 SAS exome AF: 0.0378

Gnomad4 FIN exome AF: 0.00923

Gnomad4 NFE exome AF: 0.0124

Gnomad4 OTH exome AF: 0.0239

GnomAD4 genome AF: 0.0389 AC: 5928 AN: 152314 Hom.: 225 Cov.: 32 AF XY: 0.0387 AC XY: 2886 AN XY: 74482

Gnomad4 AFR AF: 0.0789

Gnomad4 AMR AF: 0.0288

Gnomad4 ASJ AF: 0.0118

Gnomad4 EAS AF: 0.165

Gnomad4 SAS AF: 0.0419

Gnomad4 FIN AF: 0.00922

Gnomad4 NFE AF: 0.0127

Gnomad4 OTH AF: 0.0294

Alfa AF: 0.0225 Hom.: 180

Bravo AF: 0.0443

TwinsUK AF: 0.0129 AC: 48

ALSPAC AF: 0.0109 AC: 42

ESP6500AA AF: 0.0844 AC: 372

ESP6500EA AF: 0.0128 AC: 110

ExAC AF: 0.0379 AC: 4602

Asia WGS AF: 0.0870 AC: 301 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -

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

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	13
DANN	Benign	0.95
DEOGEN2	Benign	0.37	T;.
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.78	T;T
MetaRNN	Benign	0.00085	T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	0.69	N;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.41	N;N
REVEL	Benign	0.22
Sift	Uncertain	0.0050	D;D
Sift4G	Benign	0.15	T;T
Polyphen		0.0060	B;.
Vest4		0.019
MPC		0.15
ClinPred		0.010	T
GERP RS		-2.2
Varity_R		0.082
gMVP		0.51

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

Publications

LitVar

Other links and lift over

dbSNP: rs72869687; hg19: chr3-38888735; COSMIC: COSV56570947; COSMIC: COSV56570947;