2-166443618-T-C

Position:

chr2-166443618-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002976.4(SCN7A):c.1685A>G(p.Tyr562Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00234 in 1,571,524 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0045 ( 12 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 51 hom. )

Consequence

SCN7A
NM_002976.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 3.43

Variant links:

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 links:

SCN7A (HGNC:):

SCN7A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009020597).

BP6

Variant 2-166443618-T-C is Benign according to our data. Variant chr2-166443618-T-C is described in ClinVar as [Benign]. Clinvar id is 445875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-166443618-T-C is described in Lovd as [Likely_benign]. Variant chr2-166443618-T-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00447 (681/152322) while in subpopulation AMR AF= 0.0326 (499/15292). AF 95% confidence interval is 0.0303. There are 12 homozygotes in gnomad4. There are 396 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN7A	NM_002976.4 linkuse as main transcript	c.1685A>G	p.Tyr562Cys	missense_variant	14/26	ENST00000643258.1	NP_002967.2	Q01118

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SCN7A	ENST00000643258.1 linkuse as main transcript	c.1685A>G	p.Tyr562Cys	missense_variant	14/26		NM_002976.4	ENSP00000496114.1	Q01118
SCN7A	ENST00000441411.2 linkuse as main transcript	c.1685A>G	p.Tyr562Cys	missense_variant	13/25	1		ENSP00000403846.2	Q01118
SCN7A	ENST00000424326.5 linkuse as main transcript	n.1685A>G		non_coding_transcript_exon_variant	13/26	1		ENSP00000396600.1	F8WD82
SCN7A	ENST00000419992.6 linkuse as main transcript	c.1685A>G	p.Tyr562Cys	missense_variant	14/15	5		ENSP00000413699.2	C9JW43

Frequencies

GnomAD3 genomes

AF:

0.00448

AC:

682

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00104

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0327

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.0102

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.00311

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000353

Gnomad OTH

AF:

0.0110

GnomAD3 exomes

AF:

0.00743

AC:

1383

AN:

186260

Hom.:

AF XY:

0.00591

AC XY:

586

AN XY:

99108

show subpopulations

Gnomad AFR exome

AF:

0.00116

Gnomad AMR exome

AF:

0.0419

Gnomad ASJ exome

AF:

0.000562

Gnomad EAS exome

AF:

0.00727

Gnomad SAS exome

AF:

0.000594

Gnomad FIN exome

AF:

0.00443

Gnomad NFE exome

AF:

0.000468

Gnomad OTH exome

AF:

0.00797

GnomAD4 exome

AF:

0.00212

AC:

3003

AN:

1419202

Hom.:

Cov.:

AF XY:

0.00192

AC XY:

1351

AN XY:

701912

show subpopulations

Gnomad4 AFR exome

AF:

0.000674

Gnomad4 AMR exome

AF:

0.0406

Gnomad4 ASJ exome

AF:

0.000789

Gnomad4 EAS exome

AF:

0.0215

Gnomad4 SAS exome

AF:

0.000450

Gnomad4 FIN exome

AF:

0.00405

Gnomad4 NFE exome

AF:

0.000196

Gnomad4 OTH exome

AF:

0.00243

GnomAD4 genome

AF:

0.00447

AC:

681

AN:

152322

Hom.:

Cov.:

AF XY:

0.00532

AC XY:

396

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00103

Gnomad4 AMR

AF:

0.0326

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.0102

Gnomad4 SAS

AF:

0.000828

Gnomad4 FIN

AF:

0.00311

Gnomad4 NFE

AF:

0.000353

Gnomad4 OTH

AF:

0.0104

Alfa

AF:

0.000856

Hom.:

Bravo

AF:

0.00700

ESP6500AA

AF:

0.000823

AC:

ESP6500EA

AF:

0.000613

AC:

ExAC

AF:

0.00436

AC:

519

Asia WGS

AF:

0.0110

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.015

BayesDel_noAF

Pathogenic

0.24

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.79

D;D;D;D;D;D

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.99

.;D;.;.;.;D

MetaRNN

Benign

0.0090

T;T;T;T;T;T

MetaSVM

Uncertain

0.41

MutationAssessor

Uncertain

2.4

M;M;M;M;M;.

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-8.4

.;.;D;.;.;D

REVEL

Pathogenic

0.72

Sift

Pathogenic

0.0

.;.;D;.;.;D

Sift4G

Pathogenic

0.0

D;D;D;.;.;D

Polyphen

1.0

D;D;D;D;D;.

Vest4

0.69

MVP

0.99

MPC

0.27

ClinPred

0.036

GERP RS

4.9

Varity_R

0.84

gMVP

0.42

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over