2-107988201-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_021815.5(SLC5A7):c.46C>T(p.Leu16Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00138 in 1,614,090 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L16I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00098 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (5 hom.)
• Consequence: SLC5A7 NM_021815.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 0.789

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.024518013).
• BP6: Variant 2-107988201-C-T is Benign according to our data. Variant chr2-107988201-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 464174.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=5}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000985 (150/152296) while in subpopulation SAS AF= 0.0027 (13/4822). AF 95% confidence interval is 0.00159. There are 0 homozygotes in gnomad4. There are 74 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC5A7	NM_021815.5	c.46C>T	p.Leu16Phe	missense_variant	2/9	ENST00000264047.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC5A7	ENST00000264047.3	c.46C>T	p.Leu16Phe	missense_variant	2/9	1	NM_021815.5	P1
SLC5A7	ENST00000409059.5	c.46C>T	p.Leu16Phe	missense_variant	2/9	1		P1

Frequencies

GnomAD3 genomes AF: 0.000986 AC: 150 AN: 152178 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00140

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00175 AC: 440 AN: 251474 Hom.: 1 AF XY: 0.00197 AC XY: 268 AN XY: 135908

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00320

Gnomad FIN exome AF: 0.00176

Gnomad NFE exome AF: 0.00241

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00142 AC: 2071 AN: 1461794 Hom.: 5 Cov.: 30 AF XY: 0.00151 AC XY: 1099 AN XY: 727210

Gnomad4 AFR exome AF: 0.000358

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.000918

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00299

Gnomad4 FIN exome AF: 0.00195

Gnomad4 NFE exome AF: 0.00139

Gnomad4 OTH exome AF: 0.00146

GnomAD4 genome AF: 0.000985 AC: 150 AN: 152296 Hom.: 0 Cov.: 33 AF XY: 0.000994 AC XY: 74 AN XY: 74458

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00140

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00135 Hom.: 0

Bravo AF: 0.000899

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.00204 AC: 248

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00224

EpiControl AF: 0.00207

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 07, 2023	See Variant Classification Assertion Criteria. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 20, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 07, 2022	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Neuronopathy, distal hereditary motor, type 7A;C4310694:Congenital myasthenic syndrome 20 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

SLC5A7-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 14, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.050
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D;D
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.83	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.025	T;T
MetaSVM	Uncertain	0.43	D
MutationAssessor	Uncertain	2.8	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0060	D;D
Sift4G	Benign	0.074	T;T
Polyphen		0.34	B;B
Vest4		0.41
MVP		0.71
MPC		0.99
ClinPred		0.030	T
GERP RS		5.7
Varity_R		0.34
gMVP		0.83

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

Other links and lift over

dbSNP: rs143876748; hg19: chr2-108604657; COSMIC: COSV50895379;