rs2241941

Positions:

• chr11-20601477-C-A
• chr11-20601477-C-G
• chr11-20601477-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004211.5(SLC6A5):​c.352C>A​(p.Leu118Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict 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. L118R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: SLC6A5 NM_004211.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.752

Genes affected

SLC6A5 (HGNC:11051): (solute carrier family 6 member 5) This gene encodes a sodium- and chloride-dependent glycine neurotransmitter transporter. This integral membrane glycoprotein is responsible for the clearance of extracellular glycine during glycine-mediated neurotransmission. This protein is found in glycinergic axons and maintains a high presynaptic pool of neurotransmitter at glycinergic synapses. Mutations in this gene cause hyperekplexia; a heterogenous neurological disorder characterized by exaggerated startle responses and neonatal apnea. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.052518636).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A5	NM_004211.5	c.352C>A	p.Leu118Met	missense_variant	2/16	ENST00000525748.6
SLC6A5	NM_001318369.2	c.-212C>A		5_prime_UTR_variant	2/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A5	ENST00000525748.6	c.352C>A	p.Leu118Met	missense_variant	2/16	1	NM_004211.5	P1
SLC6A5	ENST00000298923.11	c.352C>A	p.Leu118Met	missense_variant, NMD_transcript_variant	2/15	1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 71

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.033	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	0.99	P
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.078
Sift	Benign	0.18	T
Sift4G	Benign	0.27	T
Polyphen		0.0	B
Vest4		0.22
MutPred		0.26		Gain of loop (P = 0.1081);
MVP		0.32
MPC		0.19
ClinPred		0.056	T
GERP RS		1.7
Varity_R		0.12
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs2241941; hg19: chr11-20623023;