11-20654773-G-C

Variant names:

• chr11-20654773-G-C
• rs16906628
• NM_004211.5:c.2299G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004211.5(SLC6A5):​c.2299G>C​(p.Gly767Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G767E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SLC6A5 NM_004211.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.54
• Publications: 0 publications found

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]

SLC6A5 Gene-Disease associations (from GenCC):

• hyperekplexia 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• hereditary hyperekplexia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3947942).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A5	NM_004211.5	c.2299G>C	p.Gly767Arg	missense_variant	Exon 16 of 16	ENST00000525748.6	NP_004202.4
SLC6A5	NM_001318369.2	c.1597G>C	p.Gly533Arg	missense_variant	Exon 15 of 15		NP_001305298.1
SLC6A5	XM_017018544.3	c.1423G>C	p.Gly475Arg	missense_variant	Exon 12 of 12		XP_016874033.1
SLC6A5	XR_007062528.1	n.1677G>C		non_coding_transcript_exon_variant	Exon 13 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A5	ENST00000525748.6	c.2299G>C	p.Gly767Arg	missense_variant	Exon 16 of 16	1	NM_004211.5	ENSP00000434364.2
SLC6A5	ENST00000298923.11	n.*1596G>C		non_coding_transcript_exon_variant	Exon 15 of 15	1		ENSP00000298923.7
SLC6A5	ENST00000298923.11	n.*1596G>C		3_prime_UTR_variant	Exon 15 of 15	1		ENSP00000298923.7
SLC6A5	ENST00000528440.1	n.830G>C		non_coding_transcript_exon_variant	Exon 8 of 8	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461868 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727236

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111988

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.032	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.6	L
PhyloP100		9.5
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.47
Sift	Benign	0.12	T
Sift4G	Benign	0.19	T
Polyphen		0.90	P
Vest4		0.28
MutPred		0.52		Loss of ubiquitination at K771 (P = 0.0328);
MVP		0.89
MPC		0.39
ClinPred		0.97	D
GERP RS		5.9
Varity_R		0.33
gMVP		0.88
Mutation Taster		=74/26	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: rs16906628; hg19: chr11-20676319;