rs142776152

Positions:

chr2-108002012-A-G

Variant summary

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

The NM_021815.5(SLC5A7):c.713A>G(p.Tyr238Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00215 in 1,613,914 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0025 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 13 hom. )

Consequence

SLC5A7
NM_021815.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.27

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 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=0.010718852).

BP6

Variant 2-108002012-A-G is Benign according to our data. Variant chr2-108002012-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 464175.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-108002012-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00253 (385/152096) while in subpopulation SAS AF= 0.00478 (23/4816). AF 95% confidence interval is 0.00326. There are 2 homozygotes in gnomad4. There are 239 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC5A7	NM_021815.5 linkuse as main transcript	c.713A>G	p.Tyr238Cys	missense_variant	6/9	ENST00000264047.3	NP_068587.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC5A7	ENST00000264047.3 linkuse as main transcript	c.713A>G	p.Tyr238Cys	missense_variant	6/9	1	NM_021815.5	ENSP00000264047	P1
SLC5A7	ENST00000409059.5 linkuse as main transcript	c.713A>G	p.Tyr238Cys	missense_variant	6/9	1		ENSP00000387346	P1

Frequencies

GnomAD3 genomes

AF:

0.00253

AC:

385

AN:

151978

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00340

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00477

Gnomad FIN

AF:

0.0162

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00176

Gnomad OTH

AF:

0.00240

GnomAD3 exomes

AF:

0.00282

AC:

710

AN:

251434

Hom.:

AF XY:

0.00283

AC XY:

384

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00174

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00196

Gnomad FIN exome

AF:

0.0157

Gnomad NFE exome

AF:

0.00200

Gnomad OTH exome

AF:

0.00293

GnomAD4 exome

AF:

0.00211

AC:

3082

AN:

1461818

Hom.:

Cov.:

AF XY:

0.00215

AC XY:

1563

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.000388

Gnomad4 AMR exome

AF:

0.00219

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00209

Gnomad4 FIN exome

AF:

0.0155

Gnomad4 NFE exome

AF:

0.00166

Gnomad4 OTH exome

AF:

0.00187

GnomAD4 genome

AF:

0.00253

AC:

385

AN:

152096

Hom.:

Cov.:

AF XY:

0.00321

AC XY:

239

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.00340

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00478

Gnomad4 FIN

AF:

0.0162

Gnomad4 NFE

AF:

0.00176

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00192

Hom.:

Bravo

AF:

0.00176

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.00292

AC:

355

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00153

EpiControl

AF:

0.00142

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 28, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 27, 2023	See Variant Classification Assertion Criteria. -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	SLC5A7: BS1, BS2 -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.17

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.22

T;T

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.047

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.76

.;T

MetaRNN

Benign

0.011

T;T

MetaSVM

Benign

-0.55

MutationAssessor

Benign

-0.34

N;N

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.99

N;N

REVEL

Uncertain

0.50

Sift

Benign

0.14

T;T

Sift4G

Benign

0.17

T;T

Polyphen

0.0

B;B

Vest4

0.67

MVP

0.88

MPC

1.0

ClinPred

0.016

GERP RS

4.2

Varity_R

0.12

gMVP

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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