rs142776152

Variant names:

• chr2-108002012-A-G
• rs142776152
• NM_021815.5:c.713A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001305007.3(SLC5A7):​c.-29A>G variant causes a 5 prime UTR premature start codon gain 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. 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_001305007.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.27
• Publications: 6 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 (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 Benign/Likely_benign. ClinVar VariationId is 464175.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001305007.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC5A7	NM_021815.5	MANE Select	c.713A>G	p.Tyr238Cys	missense	Exon 6 of 9	NP_068587.1
	SLC5A7	NM_001305007.3		c.-29A>G		5_prime_UTR_premature_start_codon_gain	Exon 6 of 9	NP_001291936.1
	SLC5A7	NM_001305005.3		c.713A>G	p.Tyr238Cys	missense	Exon 6 of 9	NP_001291934.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC5A7	ENST00000264047.3	TSL:1 MANE Select	c.713A>G	p.Tyr238Cys	missense	Exon 6 of 9	ENSP00000264047.2
	SLC5A7	ENST00000409059.5	TSL:1	c.713A>G	p.Tyr238Cys	missense	Exon 6 of 9	ENSP00000387346.1
	SLC5A7	ENST00000950055.1		c.599A>G	p.Tyr200Cys	missense	Exon 5 of 8	ENSP00000620114.1

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

GnomAD2 exomes AF: 0.00282 AC: 710 AN: 251434 AF XY: 0.00283

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 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

African (AFR) AF: 0.000388 AC: 13 AN: 33480

American (AMR) AF: 0.00219 AC: 98 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00209 AC: 180 AN: 86254

European-Finnish (FIN) AF: 0.0155 AC: 826 AN: 53416

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5762

European-Non Finnish (NFE) AF: 0.00166 AC: 1845 AN: 1111956

Other (OTH) AF: 0.00187 AC: 113 AN: 60394

GnomAD4 genome AF: 0.00253 AC: 385 AN: 152096 Hom.: 2 Cov.: 32 AF XY: 0.00321 AC XY: 239 AN XY: 74340

African (AFR) AF: 0.000313 AC: 13 AN: 41472

American (AMR) AF: 0.00340 AC: 52 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00478 AC: 23 AN: 4816

European-Finnish (FIN) AF: 0.0162 AC: 171 AN: 10568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00176 AC: 120 AN: 68000

Other (OTH) AF: 0.00237 AC: 5 AN: 2106

Alfa AF: 0.00199 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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Neuronopathy, distal hereditary motor, type 7A;C4310694:Congenital myasthenic syndrome 20 (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.047
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	-0.34	N
PhyloP100		3.3
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.99	N
REVEL	Uncertain	0.50
Sift	Benign	0.14	T
Sift4G	Benign	0.17	T
Polyphen		0.0	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
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs142776152; hg19: chr2-108618468;