2-166406082-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_002976.4(SCN7A):c.4547G>A(p.Arg1516Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00658 in 1,612,390 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0045 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0068 (46 hom.)
• Consequence: SCN7A NM_002976.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.77

Genes affected

SCN7A (HGNC:10594): (sodium voltage-gated channel alpha subunit 7) This gene encodes one of the many voltage-gated sodium channel proteins. For proper functioning of neurons and muscles during action potentials, voltage-gated sodium channels direct sodium ion diffusion for membrane depolarization. This sodium channel protein has some atypical characteristics; the similarity between the human and mouse proteins is lower compared to other orthologous sodium channel pairs. Also, the S4 segments, which sense voltage changes, have fewer positive charged residues that in other sodium channels; domain 4 has fewer arginine and lysine residues compared to other sodium channel proteins. Several alternatively spliced transcript variants exist, but the full-length natures of all of them remain unknown. [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0068476796).
• BP6: Variant 2-166406082-C-T is Benign according to our data. Variant chr2-166406082-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 709139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-166406082-C-T is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN7A	NM_002976.4	c.4547G>A	p.Arg1516Lys	missense_variant	26/26	ENST00000643258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN7A	ENST00000643258.1	c.4547G>A	p.Arg1516Lys	missense_variant	26/26		NM_002976.4	P1
SCN7A	ENST00000441411.2	c.4547G>A	p.Arg1516Lys	missense_variant	25/25	1		P1
SCN7A	ENST00000424326.5	c.*2352G>A		3_prime_UTR_variant, NMD_transcript_variant	26/26	1

Frequencies

GnomAD3 genomes AF: 0.00448 AC: 681 AN: 151844 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00114

Gnomad AMI AF: 0.0220

Gnomad AMR AF: 0.000592

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00283

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00826

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00376 AC: 927 AN: 246420 Hom.: 1 AF XY: 0.00389 AC XY: 520 AN XY: 133800

Gnomad AFR exome AF: 0.00104

Gnomad AMR exome AF: 0.00105

Gnomad ASJ exome AF: 0.000800

Gnomad EAS exome AF: 0.0000563

Gnomad SAS exome AF: 0.000819

Gnomad FIN exome AF: 0.00303

Gnomad NFE exome AF: 0.00679

Gnomad OTH exome AF: 0.00353

GnomAD4 exome AF: 0.00680 AC: 9930 AN: 1460428 Hom.: 46 Cov.: 33 AF XY: 0.00661 AC XY: 4800 AN XY: 726470

Gnomad4 AFR exome AF: 0.000987

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.000613

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000997

Gnomad4 FIN exome AF: 0.00396

Gnomad4 NFE exome AF: 0.00831

Gnomad4 OTH exome AF: 0.00486

GnomAD4 genome AF: 0.00448 AC: 681 AN: 151962 Hom.: 1 Cov.: 32 AF XY: 0.00408 AC XY: 303 AN XY: 74280

Gnomad4 AFR AF: 0.00113

Gnomad4 AMR AF: 0.000591

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00283

Gnomad4 NFE AF: 0.00826

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00611 Hom.: 9

Bravo AF: 0.00437

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.00137 AC: 5

ESP6500EA AF: 0.00745 AC: 61

ExAC AF: 0.00382 AC: 461

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

SCN7A-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 01, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	15
Dann	Benign	0.97
DEOGEN2	Benign	0.20	T;T;T;T;T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.46	N
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.0068	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L;L;L;L;L
MutationTaster	Benign	0.97	N
PrimateAI	Benign	0.29	T
Sift4G	Uncertain	0.0050	D;D;D;.;.
Polyphen		0.0020	B;B;B;B;B
Vest4		0.12
MVP		0.32
MPC		0.035
ClinPred		0.016	T
GERP RS		1.3
Varity_R		0.073
gMVP		0.45

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: rs34799257; hg19: chr2-167262592; COSMIC: COSV99081468;