2-107992192-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_021815.5(SLC5A7):c.265A>G(p.Ile89Val) variant causes a missense change. The variant allele was found at a frequency of 0.0844 in 1,612,352 control chromosomes in the GnomAD database, including 6,649 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I89T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.075 ( 582 hom., cov: 32)

Exomes 𝑓: 0.085 ( 6067 hom. )

Consequence

SLC5A7
NM_021815.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 5.23

Publications

53 publications found

Variant links:

Genes affected

SLC5A7 (HGNC:14025): (solute carrier family 5 member 7) This gene encodes a sodium ion- and chloride ion-dependent high-affinity transporter that mediates choline uptake for acetylcholine synthesis in cholinergic neurons. The protein transports choline from the extracellular space into presynaptic terminals for synthesis into acetylcholine. Increased choline uptake results from increased density of this protein in synaptosomal plasma membranes in response to depolarization of cholinergic terminals. Dysfunction of cholinergic signaling has been implicated in various disorders including depression, attention-deficit disorder, and schizophrenia. An allelic variant of this gene is associated with autosomal dominant distal hereditary motor neuronopathy type VIIA. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2015]

SLC5A7 Gene-Disease associations (from GenCC):

neuronopathy, distal hereditary motor, type 7A
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
congenital myasthenic syndrome 20
Inheritance: AR Classification: STRONG Submitted by: G2P, Ambry Genetics, PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
distal hereditary motor neuropathy type 7
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
presynaptic congenital myasthenic syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SLC5A7 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=0.002653569).

BP6

Variant 2-107992192-A-G is Benign according to our data. Variant chr2-107992192-A-G is described in ClinVar as Benign. ClinVar VariationId is 261428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.142 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC5A7	NM_021815.5 link	c.265A>G	p.Ile89Val	missense_variant	Exon 3 of 9	ENST00000264047.3	NP_068587.1	Q9GZV3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC5A7	ENST00000264047.3 link	c.265A>G	p.Ile89Val	missense_variant	Exon 3 of 9	1	NM_021815.5	ENSP00000264047.2		Q9GZV3
SLC5A7	ENST00000409059.5 link	c.265A>G	p.Ile89Val	missense_variant	Exon 3 of 9	1		ENSP00000387346.1		Q9GZV3

Frequencies

GnomAD3 genomes

AF:

0.0750

AC:

11415

AN:

152192

Hom.:

578

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0266

Gnomad AMI

AF:

0.0822

Gnomad AMR

AF:

0.146

Gnomad ASJ

AF:

0.0487

Gnomad EAS

AF:

0.126

Gnomad SAS

AF:

0.0331

Gnomad FIN

AF:

0.116

Gnomad MID

AF:

0.0191

Gnomad NFE

AF:

0.0829

Gnomad OTH

AF:

0.0628

GnomAD2 exomes

AF:

0.0926

AC:

23270

AN:

251232

AF XY:

0.0865

show subpopulations

Gnomad AFR exome

AF:

0.0241

Gnomad AMR exome

AF:

0.204

Gnomad ASJ exome

AF:

0.0517

Gnomad EAS exome

AF:

0.124

Gnomad FIN exome

AF:

0.119

Gnomad NFE exome

AF:

0.0798

Gnomad OTH exome

AF:

0.0842

GnomAD4 exome

AF:

0.0854

AC:

124643

AN:

1460042

Hom.:

6067

Cov.:

AF XY:

0.0834

AC XY:

60568

AN XY:

726466

show subpopulations

African (AFR)

AF:

0.0231

AC:

772

AN:

33458

American (AMR)

AF:

0.200

AC:

8933

AN:

44670

Ashkenazi Jewish (ASJ)

AF:

0.0506

AC:

1321

AN:

26116

East Asian (EAS)

AF:

0.127

AC:

5038

AN:

39638

South Asian (SAS)

AF:

0.0286

AC:

2465

AN:

86210

European-Finnish (FIN)

AF:

0.115

AC:

6159

AN:

53386

Middle Eastern (MID)

AF:

0.0214

AC:

123

AN:

5758

European-Non Finnish (NFE)

AF:

0.0858

AC:

95269

AN:

1110486

Other (OTH)

AF:

0.0756

AC:

4563

AN:

60320

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

4818

9637

14455

19274

24092

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3640

7280

10920

14560

18200

<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:

0.0750

AC:

11421

AN:

152310

Hom.:

582

Cov.:

AF XY:

0.0767

AC XY:

5711

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.0265

AC:

1103

AN:

41582

American (AMR)

AF:

0.147

AC:

2245

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0487

AC:

169

AN:

3472

East Asian (EAS)

AF:

0.126

AC:

655

AN:

5184

South Asian (SAS)

AF:

0.0329

AC:

159

AN:

4828

European-Finnish (FIN)

AF:

0.116

AC:

1236

AN:

10614

Middle Eastern (MID)

AF:

0.0240

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0829

AC:

5641

AN:

68028

Other (OTH)

AF:

0.0621

AC:

131

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

536

1072

1608

2144

2680

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

124

248

372

496

620

<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:

0.0783

Hom.:

912

Bravo

AF:

0.0778

TwinsUK

AF:

0.0868

AC:

322

ALSPAC

AF:

0.0960

AC:

370

ESP6500AA

AF:

0.0286

AC:

126

ESP6500EA

AF:

0.0814

AC:

700

ExAC

AF:

0.0839

AC:

10192

Asia WGS

AF:

0.0740

AC:

258

AN:

3478

EpiCase

AF:

0.0776

EpiControl

AF:

0.0687

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Sep 11, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 12237312) -

Nov 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Neuronopathy, distal hereditary motor, type 7A;C4310694:Congenital myasthenic syndrome 20

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.70

DEOGEN2

Benign

0.11

T;T

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.89

.;D

MetaRNN

Benign

0.0027

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.47

N;N

PhyloP100

5.2

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.44

N;N

REVEL

Uncertain

0.32

Sift

Benign

0.44

T;T

Sift4G

Benign

0.76

T;T

Polyphen

0.015

B;B

Vest4

0.045

MPC

0.70

ClinPred

0.012

GERP RS

3.8

Varity_R

0.10

gMVP

0.65

Mutation Taster

=292/8

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over