11-20601496-T-C

Position:

• chr11-20601496-T-C

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.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. 15/20 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

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=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 id is 304008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-20601496-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.869 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC6A5	NM_004211.5	c.371T>C	p.Phe124Ser	missense_variant	2/16	ENST00000525748.6	NP_004202.4
SLC6A5	NM_001318369.2	c.-193T>C		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.371T>C	p.Phe124Ser	missense_variant	2/16	1	NM_004211.5	ENSP00000434364	P1
SLC6A5	ENST00000298923.11	c.371T>C	p.Phe124Ser	missense_variant, NMD_transcript_variant	2/15	1		ENSP00000298923

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

GnomAD3 exomes AF: 0.771 AC: 191211 AN: 247878 Hom.: 73852 AF XY: 0.771 AC XY: 103604 AN XY: 134390

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 SAS exome AF: 0.789

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

Gnomad4 AFR exome AF: 0.878

Gnomad4 AMR exome AF: 0.750

Gnomad4 ASJ exome AF: 0.816

Gnomad4 EAS exome AF: 0.792

Gnomad4 SAS exome AF: 0.790

Gnomad4 FIN exome AF: 0.745

Gnomad4 NFE exome AF: 0.758

Gnomad4 OTH exome AF: 0.764

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

Gnomad4 AFR AF: 0.877

Gnomad4 AMR AF: 0.757

Gnomad4 ASJ AF: 0.803

Gnomad4 EAS AF: 0.761

Gnomad4 SAS AF: 0.790

Gnomad4 FIN AF: 0.742

Gnomad4 NFE AF: 0.758

Gnomad4 OTH AF: 0.766

Alfa AF: 0.768 Hom.: 116525

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

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	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

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	0.056
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
MutationTaster	Benign	1.0	P
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

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

LitVar

Other links and lift over

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