11-20601496-T-C

Variant names:

• chr11-20601496-T-C
• rs1443548
• NM_004211.5:c.371T>C

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.371T>C​(p.Phe124Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.767 in 1,613,190 control chromosomes in the GnomAD database, including 475,594 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.79 (48038 hom., cov: 34)
  • Exomes 𝑓: 0.76 (427556 hom.)
• Consequence: SLC6A5 NM_004211.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.06
• Publications: 31 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=7.56026E-7).
• BP6: Variant 11-20601496-T-C is Benign according to our data. Variant chr11-20601496-T-C is described in ClinVar as Benign. ClinVar VariationId is 304008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.869 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004211.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A5	NM_004211.5	MANE Select	c.371T>C	p.Phe124Ser	missense	Exon 2 of 16	NP_004202.4
	SLC6A5	NM_001318369.2		c.-193T>C		5_prime_UTR	Exon 2 of 15	NP_001305298.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A5	ENST00000525748.6	TSL:1 MANE Select	c.371T>C	p.Phe124Ser	missense	Exon 2 of 16	ENSP00000434364.2
	SLC6A5	ENST00000298923.11	TSL:1	n.371T>C		non_coding_transcript_exon	Exon 2 of 15	ENSP00000298923.7

Frequencies

GnomAD3 genomes AF: 0.792 AC: 120486 AN: 152072 Hom.: 47993 Cov.: 34

Gnomad AFR AF: 0.877

Gnomad AMI AF: 0.934

Gnomad AMR AF: 0.758

Gnomad ASJ AF: 0.803

Gnomad EAS AF: 0.761

Gnomad SAS AF: 0.789

Gnomad FIN AF: 0.742

Gnomad MID AF: 0.741

Gnomad NFE AF: 0.758

Gnomad OTH AF: 0.765

GnomAD2 exomes AF: 0.771 AC: 191211 AN: 247878 AF XY: 0.771

Gnomad AFR exome AF: 0.877

Gnomad AMR exome AF: 0.750

Gnomad ASJ exome AF: 0.817

Gnomad EAS exome AF: 0.759

Gnomad FIN exome AF: 0.743

Gnomad NFE exome AF: 0.762

Gnomad OTH exome AF: 0.761

GnomAD4 exome AF: 0.764 AC: 1116844 AN: 1461000 Hom.: 427556 Cov.: 79 AF XY: 0.765 AC XY: 555791 AN XY: 726766

African (AFR) AF: 0.878 AC: 29396 AN: 33468

American (AMR) AF: 0.750 AC: 33408 AN: 44552

Ashkenazi Jewish (ASJ) AF: 0.816 AC: 21324 AN: 26118

East Asian (EAS) AF: 0.792 AC: 31403 AN: 39670

South Asian (SAS) AF: 0.790 AC: 68070 AN: 86182

European-Finnish (FIN) AF: 0.745 AC: 39709 AN: 53328

Middle Eastern (MID) AF: 0.777 AC: 4483 AN: 5766

European-Non Finnish (NFE) AF: 0.758 AC: 842964 AN: 1111582

Other (OTH) AF: 0.764 AC: 46087 AN: 60334

GnomAD4 genome AF: 0.792 AC: 120586 AN: 152190 Hom.: 48038 Cov.: 34 AF XY: 0.790 AC XY: 58769 AN XY: 74404

African (AFR) AF: 0.877 AC: 36428 AN: 41550

American (AMR) AF: 0.757 AC: 11588 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.803 AC: 2787 AN: 3472

East Asian (EAS) AF: 0.761 AC: 3928 AN: 5160

South Asian (SAS) AF: 0.790 AC: 3812 AN: 4826

European-Finnish (FIN) AF: 0.742 AC: 7853 AN: 10590

Middle Eastern (MID) AF: 0.738 AC: 217 AN: 294

European-Non Finnish (NFE) AF: 0.758 AC: 51502 AN: 67974

Other (OTH) AF: 0.766 AC: 1619 AN: 2114

Alfa AF: 0.773 Hom.: 167672

Bravo AF: 0.798

TwinsUK AF: 0.755 AC: 2801

ALSPAC AF: 0.754 AC: 2905

ESP6500AA AF: 0.874 AC: 3850

ESP6500EA AF: 0.755 AC: 6490

ExAC AF: 0.773 AC: 93712

Asia WGS AF: 0.781 AC: 2718 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperekplexia 3 Benign:3

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

May 28, 2019

Mendelics

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	18
DANN	Benign	0.91
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.076	T
MetaRNN	Benign	7.6e-7	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.1
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.72	N
REVEL	Benign	0.14
Sift	Benign	0.44	T
Sift4G	Benign	0.41	T
Polyphen		0.0	B
Vest4		0.025
MPC		0.34
ClinPred		0.0031	T
GERP RS		2.8
Varity_R		0.050
gMVP		0.50
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1443548; hg19: chr11-20623042; COSMIC: COSV54229272;