chr2-166405701-C-T

Position:

• chr2-166405701-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_002976.4(SCN7A):​c.4928G>A​(p.Arg1643Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000184 in 1,612,994 control chromosomes in the GnomAD database, including 1 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 (★).

• Frequency:
  • Genomes: 𝑓 0.00091 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (1 hom.)
• Consequence: SCN7A NM_002976.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.14

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]

SCN7A (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.00546962).
• BP6: Variant 2-166405701-C-T is Benign according to our data. Variant chr2-166405701-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 713051.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN7A	NM_002976.4	c.4928G>A	p.Arg1643Gln	missense_variant	26/26	ENST00000643258.1	NP_002967.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN7A	ENST00000643258.1	c.4928G>A	p.Arg1643Gln	missense_variant	26/26		NM_002976.4	ENSP00000496114.1
SCN7A	ENST00000441411.2	c.4928G>A	p.Arg1643Gln	missense_variant	25/25	1		ENSP00000403846.2
SCN7A	ENST00000424326.5	n.*2733G>A		non_coding_transcript_exon_variant	26/26	1		ENSP00000396600.1
SCN7A	ENST00000424326.5	n.*2733G>A		3_prime_UTR_variant	26/26	1		ENSP00000396600.1

Frequencies

GnomAD3 genomes AF: 0.000908 AC: 138 AN: 152030 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000213 AC: 53 AN: 248258 Hom.: 0 AF XY: 0.000163 AC XY: 22 AN XY: 134696

Gnomad AFR exome AF: 0.00304

Gnomad AMR exome AF: 0.0000582

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000109 AC: 159 AN: 1460846 Hom.: 1 Cov.: 33 AF XY: 0.0000922 AC XY: 67 AN XY: 726718

Gnomad4 AFR exome AF: 0.00305

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000333

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000907 AC: 138 AN: 152148 Hom.: 0 Cov.: 32 AF XY: 0.000914 AC XY: 68 AN XY: 74392

Gnomad4 AFR AF: 0.00313

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000736

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000194 Hom.: 0

Bravo AF: 0.00107

ESP6500AA AF: 0.00189 AC: 7

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.000290 AC: 35

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	9.8
DANN	Benign	0.74
DEOGEN2	Benign	0.31	T;T;T;T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.61	.;T;.;.;.
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.0055	T;T;T;T;T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	-0.52	N;N;N;N;N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-1.1	.;.;N;.;.
REVEL	Uncertain	0.32
Sift	Benign	0.83	.;.;T;.;.
Sift4G	Benign	0.41	T;T;T;.;.
Polyphen		0.0	B;B;B;B;B
Vest4		0.041
MVP		0.62
MPC		0.037
ClinPred		0.0046	T
GERP RS		-1.4
Varity_R		0.031
gMVP		0.14

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: rs34589606; hg19: chr2-167262211; COSMIC: COSV69271927;