rs121908496

Positions:

• chr11-20607583-C-G
• chr11-20607583-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_004211.5(SLC6A5):​c.916C>G​(p.Leu306Val) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC6A5 NM_004211.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 2.69

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-20607583-C-G is Pathogenic according to our data. Variant chr11-20607583-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 5765.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC6A5	NM_004211.5	c.916C>G	p.Leu306Val	missense_variant	5/16	ENST00000525748.6	NP_004202.4
SLC6A5	NM_001318369.2	c.214C>G	p.Leu72Val	missense_variant	4/15		NP_001305298.1
SLC6A5	XM_017018544.3	c.109+445C>G		intron_variant			XP_016874033.1
SLC6A5	XR_007062528.1	n.294C>G		non_coding_transcript_exon_variant	2/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC6A5	ENST00000525748.6	c.916C>G	p.Leu306Val	missense_variant	5/16	1	NM_004211.5	ENSP00000434364	P1
SLC6A5	ENST00000298923.11	c.*213C>G		3_prime_UTR_variant, NMD_transcript_variant	4/15	1		ENSP00000298923

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Hyperekplexia 3 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2006	- -
Pathogenic, no assertion criteria provided	curation	GeneReviews	Oct 04, 2012	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.031	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.89		Loss of catalytic residue at L306 (P = 0.2003);
MVP		0.94
MPC		0.75
ClinPred		0.99	D
GERP RS		2.8
Varity_R		0.51
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.84		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.84		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121908496; hg19: chr11-20629129;