rs1443547

Positions:

• chr11-20601429-G-A
• chr11-20601429-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004211.5(SLC6A5):​c.304G>A​(p.Gly102Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.355 in 1,604,384 control chromosomes in the GnomAD database, including 102,567 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (11666 hom., cov: 34)
  • Exomes 𝑓: 0.35 (90901 hom.)
• Consequence: SLC6A5 NM_004211.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.24

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.0244718E-4).
• BP6: Variant 11-20601429-G-A is Benign according to our data. Variant chr11-20601429-G-A is described in ClinVar as [Benign]. Clinvar id is 304002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-20601429-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.463 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC6A5	NM_004211.5	c.304G>A	p.Gly102Ser	missense_variant	2/16	ENST00000525748.6	NP_004202.4
SLC6A5	NM_001318369.2	c.-260G>A		5_prime_UTR_variant	2/15		NP_001305298.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC6A5	ENST00000525748.6	c.304G>A	p.Gly102Ser	missense_variant	2/16	1	NM_004211.5	ENSP00000434364	P1
SLC6A5	ENST00000298923.11	c.304G>A	p.Gly102Ser	missense_variant, NMD_transcript_variant	2/15	1		ENSP00000298923

Frequencies

GnomAD3 genomes AF: 0.384 AC: 58426 AN: 152068 Hom.: 11654 Cov.: 34

Gnomad AFR AF: 0.469

Gnomad AMI AF: 0.347

Gnomad AMR AF: 0.392

Gnomad ASJ AF: 0.411

Gnomad EAS AF: 0.386

Gnomad SAS AF: 0.442

Gnomad FIN AF: 0.265

Gnomad MID AF: 0.414

Gnomad NFE AF: 0.345

Gnomad OTH AF: 0.370

GnomAD3 exomes AF: 0.370 AC: 83572 AN: 226056 Hom.: 15653 AF XY: 0.372 AC XY: 45881 AN XY: 123476

Gnomad AFR exome AF: 0.470

Gnomad AMR exome AF: 0.384

Gnomad ASJ exome AF: 0.426

Gnomad EAS exome AF: 0.393

Gnomad SAS exome AF: 0.437

Gnomad FIN exome AF: 0.266

Gnomad NFE exome AF: 0.342

Gnomad OTH exome AF: 0.375

GnomAD4 exome AF: 0.352 AC: 510646 AN: 1452198 Hom.: 90901 Cov.: 61 AF XY: 0.354 AC XY: 255810 AN XY: 721666

Gnomad4 AFR exome AF: 0.475

Gnomad4 AMR exome AF: 0.382

Gnomad4 ASJ exome AF: 0.420

Gnomad4 EAS exome AF: 0.389

Gnomad4 SAS exome AF: 0.436

Gnomad4 FIN exome AF: 0.267

Gnomad4 NFE exome AF: 0.340

Gnomad4 OTH exome AF: 0.369

GnomAD4 genome AF: 0.384 AC: 58448 AN: 152186 Hom.: 11666 Cov.: 34 AF XY: 0.382 AC XY: 28403 AN XY: 74406

Gnomad4 AFR AF: 0.468

Gnomad4 AMR AF: 0.391

Gnomad4 ASJ AF: 0.411

Gnomad4 EAS AF: 0.385

Gnomad4 SAS AF: 0.443

Gnomad4 FIN AF: 0.265

Gnomad4 NFE AF: 0.345

Gnomad4 OTH AF: 0.375

Alfa AF: 0.351 Hom.: 17122

Bravo AF: 0.392

TwinsUK AF: 0.342 AC: 1269

ALSPAC AF: 0.343 AC: 1322

ESP6500AA AF: 0.436 AC: 1916

ESP6500EA AF: 0.335 AC: 2871

ExAC AF: 0.350 AC: 42097

Asia WGS AF: 0.442 AC: 1537 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperekplexia 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Hyperekplexia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.014
DANN	Benign	0.86
DEOGEN2	Benign	0.014	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.00020	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.69	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.26	N
REVEL	Benign	0.049
Sift	Benign	0.72	T
Sift4G	Benign	0.33	T
Polyphen		0.0	B
Vest4		0.018
MPC		0.19
ClinPred		0.00087	T
GERP RS		-4.0
Varity_R		0.033
gMVP		0.25

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

LitVar

Other links and lift over

dbSNP: rs1443547; hg19: chr11-20622975; COSMIC: COSV54223257;