chr11-20601262-C-G

Position:

• chr11-20601262-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004211.5(SLC6A5):​c.137C>G​(p.Pro46Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00608 in 1,583,946 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0062 (37 hom.)
• Consequence: SLC6A5 NM_004211.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.635

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=0.006926596).
• BP6: Variant 11-20601262-C-G is Benign according to our data. Variant chr11-20601262-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 303999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00462 (703/152308) while in subpopulation NFE AF= 0.00726 (494/68018). AF 95% confidence interval is 0.00673. There are 3 homozygotes in gnomad4. There are 318 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC6A5	NM_004211.5	c.137C>G	p.Pro46Arg	missense_variant	2/16	ENST00000525748.6	NP_004202.4
SLC6A5	NM_001318369.2	c.-427C>G		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.137C>G	p.Pro46Arg	missense_variant	2/16	1	NM_004211.5	ENSP00000434364.2
SLC6A5	ENST00000298923.11	n.137C>G		non_coding_transcript_exon_variant	2/15	1		ENSP00000298923.7

Frequencies

GnomAD3 genomes AF: 0.00463 AC: 705 AN: 152190 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00504

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00668

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00728

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00427 AC: 834 AN: 195416 Hom.: 0 AF XY: 0.00438 AC XY: 477 AN XY: 108888

Gnomad AFR exome AF: 0.00120

Gnomad AMR exome AF: 0.00219

Gnomad ASJ exome AF: 0.000112

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000396

Gnomad FIN exome AF: 0.00634

Gnomad NFE exome AF: 0.00760

Gnomad OTH exome AF: 0.00534

GnomAD4 exome AF: 0.00623 AC: 8924 AN: 1431638 Hom.: 37 Cov.: 31 AF XY: 0.00595 AC XY: 4231 AN XY: 710788

Gnomad4 AFR exome AF: 0.00124

Gnomad4 AMR exome AF: 0.00226

Gnomad4 ASJ exome AF: 0.0000778

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000369

Gnomad4 FIN exome AF: 0.00769

Gnomad4 NFE exome AF: 0.00739

Gnomad4 OTH exome AF: 0.00496

GnomAD4 genome AF: 0.00462 AC: 703 AN: 152308 Hom.: 3 Cov.: 33 AF XY: 0.00427 AC XY: 318 AN XY: 74482

Gnomad4 AFR AF: 0.00140

Gnomad4 AMR AF: 0.00503

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00668

Gnomad4 NFE AF: 0.00726

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00283 Hom.: 1

Bravo AF: 0.00433

ExAC AF: 0.00405 AC: 455

Asia WGS AF: 0.000578 AC: 2 AN: 3474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	SLC6A5: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 12, 2016	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hyperekplexia 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

- -

Hyperekplexia Benign:1

Likely 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	0.084
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	14
DANN	Benign	0.92
DEOGEN2	Benign	0.025	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.0	N
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.063
Sift	Benign	0.24	T
Sift4G	Benign	0.35	T
Polyphen		0.026	B
Vest4		0.30
MVP		0.71
MPC		0.21
ClinPred		0.010	T
GERP RS		3.0
Varity_R		0.036
gMVP		0.16

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: rs12364685; hg19: chr11-20622808;