Genetic Variant SLC6A5:p.Gly102Cys (chr11-20601429-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004211.5(SLC6A5):c.304G>T(p.Gly102Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. G102S) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SLC6A5
NM_004211.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.24

Publications

25 publications found

Variant links:

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

SLC6A5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=0.082791).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SLC6A5	NM_004211.5 link	c.304G>T	p.Gly102Cys	missense_variant	Exon 2 of 16	ENST00000525748.6	NP_004202.4
SLC6A5	NM_001318369.2 link	c.-260G>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 15		NP_001305298.1
SLC6A5	NM_001318369.2 link	c.-260G>T		5_prime_UTR_variant	Exon 2 of 15		NP_001305298.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A5	ENST00000525748.6 link	c.304G>T	p.Gly102Cys	missense_variant	Exon 2 of 16	1	NM_004211.5	ENSP00000434364.2
SLC6A5	ENST00000298923.11 link	n.304G>T		non_coding_transcript_exon_variant	Exon 2 of 15	1		ENSP00000298923.7

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1452510

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

721836

African (AFR)

AF:

0.00

AC:

AN:

33340

American (AMR)

AF:

0.00

AC:

AN:

43134

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25900

East Asian (EAS)

AF:

0.00

AC:

AN:

39304

South Asian (SAS)

AF:

0.00

AC:

AN:

85102

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52100

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1107892

Other (OTH)

AF:

0.00

AC:

AN:

60012

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152108

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74300

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41424

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.000207

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.725

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

25770

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

0.22

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.020

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.47

M_CAP

Benign

0.070

MetaRNN

Benign

0.083

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.0

PhyloP100

-2.2

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.59

REVEL

Benign

0.14

Sift

Benign

0.091

Sift4G

Uncertain

0.031

Vest4

0.16

ClinPred

0.14

GERP RS

-4.0

Varity_R

0.098

gMVP

0.39

Mutation Taster

=91/9

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over