2-166443618-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -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

Publications

7 publications found

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 Gene-Disease associations (from GenCC):

holoprosencephaly
Inheritance: AR Classification: LIMITED Submitted by: PanelApp Australia

SCN7A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 445875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 12 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002976.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN7A	NM_002976.4	MANE Select	c.1685A>G	p.Tyr562Cys	missense	Exon 14 of 26	NP_002967.2	Q01118
	SCN7A	NR_045628.1		n.1815A>G		non_coding_transcript_exon	Exon 13 of 26

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SCN7A	ENST00000643258.1	MANE Select	c.1685A>G	p.Tyr562Cys	missense	Exon 14 of 26	ENSP00000496114.1	Q01118
SCN7A	ENST00000441411.2	TSL:1	c.1685A>G	p.Tyr562Cys	missense	Exon 13 of 25	ENSP00000403846.2	Q01118
SCN7A	ENST00000424326.5	TSL:1	n.1685A>G		non_coding_transcript_exon	Exon 13 of 26	ENSP00000396600.1	F8WD82

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

GnomAD2 exomes

AF:

0.00743

AC:

1383

AN:

186260

AF XY:

0.00591

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 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

African (AFR)

AF:

0.000674

AC:

AN:

32634

American (AMR)

AF:

0.0406

AC:

1539

AN:

37890

Ashkenazi Jewish (ASJ)

AF:

0.000789

AC:

AN:

25348

East Asian (EAS)

AF:

0.0215

AC:

821

AN:

38198

South Asian (SAS)

AF:

0.000450

AC:

AN:

80084

European-Finnish (FIN)

AF:

0.00405

AC:

207

AN:

51098

Middle Eastern (MID)

AF:

0.000351

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.000196

AC:

213

AN:

1089446

Other (OTH)

AF:

0.00243

AC:

143

AN:

58806

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

138

276

414

552

690

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00447

AC:

681

AN:

152322

Hom.:

Cov.:

AF XY:

0.00532

AC XY:

396

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.00103

AC:

AN:

41578

American (AMR)

AF:

0.0326

AC:

499

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.000864

AC:

AN:

3472

East Asian (EAS)

AF:

0.0102

AC:

AN:

5184

South Asian (SAS)

AF:

0.000828

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00311

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000353

AC:

AN:

68022

Other (OTH)

AF:

0.0104

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

102

136

170

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00168

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.015

BayesDel_noAF

Pathogenic

0.24

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.79

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.99

MetaRNN

Benign

0.0090

MetaSVM

Uncertain

0.41

MutationAssessor

Uncertain

2.4

PhyloP100

3.4

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-8.4

REVEL

Pathogenic

0.72

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.69

MVP

0.99

MPC

0.27

ClinPred

0.036

GERP RS

4.9

Varity_R

0.84

gMVP

0.42

Mutation Taster

=92/8

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over