rs1443547

Variant names:

• chr11-20601429-G-A
• rs1443547
• NM_004211.5:c.304G>A

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G102G) has been classified as Likely 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
• Publications: 25 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: Benign. The variant received -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 VariationId is 304002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
SLC6A5	NM_004211.5	c.304G>A	p.Gly102Ser	missense_variant	Exon 2 of 16	ENST00000525748.6	NP_004202.4
SLC6A5	NM_001318369.2	c.-260G>A		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	c.304G>A	p.Gly102Ser	missense_variant	Exon 2 of 16	1	NM_004211.5	ENSP00000434364.2
SLC6A5	ENST00000298923.11	n.304G>A		non_coding_transcript_exon_variant	Exon 2 of 15	1		ENSP00000298923.7

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

GnomAD2 exomes AF: 0.370 AC: 83572 AN: 226056 AF XY: 0.372

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 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

African (AFR) AF: 0.475 AC: 15831 AN: 33332

American (AMR) AF: 0.382 AC: 16476 AN: 43104

Ashkenazi Jewish (ASJ) AF: 0.420 AC: 10881 AN: 25900

East Asian (EAS) AF: 0.389 AC: 15265 AN: 39292

South Asian (SAS) AF: 0.436 AC: 37076 AN: 85086

European-Finnish (FIN) AF: 0.267 AC: 13887 AN: 52044

Middle Eastern (MID) AF: 0.444 AC: 2544 AN: 5726

European-Non Finnish (NFE) AF: 0.340 AC: 376523 AN: 1107714

Other (OTH) AF: 0.369 AC: 22163 AN: 60000

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

African (AFR) AF: 0.468 AC: 19453 AN: 41530

American (AMR) AF: 0.391 AC: 5976 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.411 AC: 1426 AN: 3472

East Asian (EAS) AF: 0.385 AC: 1984 AN: 5154

South Asian (SAS) AF: 0.443 AC: 2140 AN: 4828

European-Finnish (FIN) AF: 0.265 AC: 2813 AN: 10606

Middle Eastern (MID) AF: 0.408 AC: 119 AN: 292

European-Non Finnish (NFE) AF: 0.345 AC: 23432 AN: 67994

Other (OTH) AF: 0.375 AC: 789 AN: 2106

Alfa AF: 0.354 Hom.: 25770

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hyperekplexia Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
PhyloP100		-2.2
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
Mutation Taster		=93/7	polymorphism (auto)

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