rs3731684

Variant names:

• chr2-108002058-C-T
• rs3731684
• NM_021815.5:c.741+18C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_021815.5(SLC5A7):​c.741+18C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,595,768 control chromosomes in the GnomAD database, including 10,120 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1471 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8649 hom.)
• Consequence: SLC5A7 NM_021815.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.325
• Publications: 5 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-108002058-C-T is Benign according to our data. Variant chr2-108002058-C-T is described in ClinVar as Benign. ClinVar VariationId is 261429.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC5A7	NM_021815.5	c.741+18C>T		intron_variant	Intron 6 of 8	ENST00000264047.3	NP_068587.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC5A7	ENST00000264047.3	c.741+18C>T		intron_variant	Intron 6 of 8	1	NM_021815.5	ENSP00000264047.2
SLC5A7	ENST00000409059.5	c.741+18C>T		intron_variant	Intron 6 of 8	1		ENSP00000387346.1

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19724 AN: 152080 Hom.: 1464 Cov.: 32

Gnomad AFR AF: 0.173

Gnomad AMI AF: 0.242

Gnomad AMR AF: 0.187

Gnomad ASJ AF: 0.0524

Gnomad EAS AF: 0.145

Gnomad SAS AF: 0.0389

Gnomad FIN AF: 0.137

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0977

Gnomad OTH AF: 0.117

GnomAD2 exomes AF: 0.123 AC: 29596 AN: 241268 AF XY: 0.113

Gnomad AFR exome AF: 0.177

Gnomad AMR exome AF: 0.251

Gnomad ASJ exome AF: 0.0591

Gnomad EAS exome AF: 0.155

Gnomad FIN exome AF: 0.139

Gnomad NFE exome AF: 0.0974

Gnomad OTH exome AF: 0.105

GnomAD4 exome AF: 0.104 AC: 150273 AN: 1443570 Hom.: 8649 Cov.: 30 AF XY: 0.101 AC XY: 72435 AN XY: 715574

African (AFR) AF: 0.177 AC: 5822 AN: 32836

American (AMR) AF: 0.243 AC: 10309 AN: 42364

Ashkenazi Jewish (ASJ) AF: 0.0544 AC: 1382 AN: 25418

East Asian (EAS) AF: 0.135 AC: 5298 AN: 39374

South Asian (SAS) AF: 0.0338 AC: 2827 AN: 83702

European-Finnish (FIN) AF: 0.130 AC: 6952 AN: 53288

Middle Eastern (MID) AF: 0.0427 AC: 241 AN: 5650

European-Non Finnish (NFE) AF: 0.101 AC: 111527 AN: 1101310

Other (OTH) AF: 0.0992 AC: 5915 AN: 59628

GnomAD4 genome AF: 0.130 AC: 19765 AN: 152198 Hom.: 1471 Cov.: 32 AF XY: 0.130 AC XY: 9685 AN XY: 74418

African (AFR) AF: 0.174 AC: 7211 AN: 41512

American (AMR) AF: 0.187 AC: 2863 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0524 AC: 182 AN: 3470

East Asian (EAS) AF: 0.145 AC: 751 AN: 5168

South Asian (SAS) AF: 0.0385 AC: 186 AN: 4830

European-Finnish (FIN) AF: 0.137 AC: 1448 AN: 10594

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0977 AC: 6643 AN: 68010

Other (OTH) AF: 0.115 AC: 244 AN: 2114

Alfa AF: 0.112 Hom.: 1738

Bravo AF: 0.139

Asia WGS AF: 0.100 AC: 346 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Sep 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.2
DANN	Benign	0.51
PhyloP100		-0.33
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3731684; hg19: chr2-108618514; COSMIC: COSV50888956;