2-108010761-G-C

Variant names:

• chr2-108010761-G-C
• rs199864231
• NM_021815.5:c.1643G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021815.5(SLC5A7):​c.1643G>C​(p.Arg548Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R548Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC5A7 NM_021815.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.32
• Publications: 2 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2468118).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021815.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC5A7	NM_021815.5	MANE Select	c.1643G>C	p.Arg548Pro	missense	Exon 9 of 9	NP_068587.1
	SLC5A7	NM_001305005.3		c.1643G>C	p.Arg548Pro	missense	Exon 9 of 9	NP_001291934.1
	SLC5A7	NM_001305006.3		c.1328G>C	p.Arg443Pro	missense	Exon 8 of 8	NP_001291935.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC5A7	ENST00000264047.3	TSL:1 MANE Select	c.1643G>C	p.Arg548Pro	missense	Exon 9 of 9	ENSP00000264047.2
	SLC5A7	ENST00000409059.5	TSL:1	c.1643G>C	p.Arg548Pro	missense	Exon 9 of 9	ENSP00000387346.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.25	T
MetaSVM	Uncertain	0.31	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.3
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.19	N
REVEL	Uncertain	0.40
Sift	Benign	0.12	T
Sift4G	Benign	0.34	T
Polyphen		0.0050	B
Vest4		0.56
MutPred		0.28		Loss of sheet (P = 0.0025)
MVP		0.91
MPC		0.047
ClinPred		0.92	D
GERP RS		6.0
Varity_R		0.22
gMVP		0.72
Mutation Taster		=51/49	polymorphism

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: rs199864231; hg19: chr2-108627217;