dbSNP rs12364685: SLC6A5:p.Pro46Gln (chr11-20601262-C-A) – 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.137C>A(p.Pro46Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000126 in 1,583,836 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. P46R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

SLC6A5
NM_004211.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.635

Publications

2 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=0.11334422).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A5	NM_004211.5 link	c.137C>A	p.Pro46Gln	missense_variant	Exon 2 of 16	ENST00000525748.6	NP_004202.4	Q9Y345-1Q4VAM4Q4VAM6
SLC6A5	NM_001318369.2 link	c.-427C>A		5_prime_UTR_variant	Exon 2 of 15		NP_001305298.1	Q9Y345-2Q4VAM4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A5	ENST00000525748.6 link	c.137C>A	p.Pro46Gln	missense_variant	Exon 2 of 16	1	NM_004211.5	ENSP00000434364.2		Q9Y345-1
SLC6A5	ENST00000298923.11 link	n.137C>A		non_coding_transcript_exon_variant	Exon 2 of 15	1		ENSP00000298923.7		J3KNC4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152190

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.98e-7

AC:

AN:

1431646

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

710794

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33180

American (AMR)

AF:

0.00

AC:

AN:

42570

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25692

East Asian (EAS)

AF:

0.00

AC:

AN:

38952

South Asian (SAS)

AF:

0.0000119

AC:

AN:

84098

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38108

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5162

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1104428

Other (OTH)

AF:

0.00

AC:

AN:

59456

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41452

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.024

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.50

M_CAP

Benign

0.026

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.34

PhyloP100

0.64

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.15

REVEL

Benign

0.066

Sift

Benign

0.36

Sift4G

Benign

0.39

Polyphen

0.026

Vest4

0.26

MutPred

0.20

Loss of catalytic residue at P46 (P = 0.0076);

MVP

0.69

MPC

0.19

ClinPred

0.11

GERP RS

3.0

Varity_R

0.039

gMVP

0.15

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over