rs142776152

chr2-108002012-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.27

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 -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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC5A7	NM_021815.5	c.713A>G	p.Tyr238Cys	missense_variant	6/9	ENST00000264047.3

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00253 AC: 385 AN: 151978 Hom.: 2 Cov.: 32

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.: 5 AF XY: 0.00283 AC XY: 384 AN XY: 135892

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.: 13 Cov.: 31 AF XY: 0.00215 AC XY: 1563 AN XY: 727206

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.: 2 Cov.: 32 AF XY: 0.00321 AC XY: 239 AN XY: 74340

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.: 1

Bravo AF: 0.00176

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00292 AC: 355

Asia WGS AF: 0.000866 AC: 3 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

Submissions by phenotype

not provided Benign:3

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 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 28, 2023	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Benign	0.22	T;T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.047
FATHMM_MKL	Uncertain	0.80	D
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	-0.34	N;N
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.57	T
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	T
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

Other links and lift over

dbSNP: rs142776152; hg19: chr2-108618468;