rs758386

Positions:

• chr3-45775926-A-G
• chr3-45775926-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020208.4(SLC6A20):​c.417T>C​(p.Cys139=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.955 in 1,614,194 control chromosomes in the GnomAD database, including 735,934 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.96 (70175 hom., cov: 32)
  • Exomes 𝑓: 0.95 (665759 hom.)
• Consequence: SLC6A20 NM_020208.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.325

Genes affected

SLC6A20 (HGNC:30927): (solute carrier family 6 member 20) Transport of small hydrophilic substances across cell membranes is mediated by substrate-specific transporter proteins which have been classified into several families of related genes. The protein encoded by this gene belongs to the sodium:neurotransmitter symporter (SNF) family and functions as a proline transporter expressed in kidney and small intestine. Mutations in this gene are associated with Hyperglycinuria and Iminoglycinuria. [provided by RefSeq, Jul 2020]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 3-45775926-A-G is Benign according to our data. Variant chr3-45775926-A-G is described in ClinVar as [Benign]. Clinvar id is 345420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-45775926-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.325 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.962 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A20	NM_020208.4	c.417T>C	p.Cys139=	synonymous_variant	4/11	ENST00000358525.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A20	ENST00000358525.9	c.417T>C	p.Cys139=	synonymous_variant	4/11	1	NM_020208.4	P1

Frequencies

GnomAD3 genomes AF: 0.960 AC: 146085 AN: 152196 Hom.: 70128 Cov.: 32

Gnomad AFR AF: 0.970

Gnomad AMI AF: 0.916

Gnomad AMR AF: 0.971

Gnomad ASJ AF: 0.978

Gnomad EAS AF: 0.917

Gnomad SAS AF: 0.951

Gnomad FIN AF: 0.948

Gnomad MID AF: 0.987

Gnomad NFE AF: 0.957

Gnomad OTH AF: 0.957

GnomAD3 exomes AF: 0.957 AC: 240558 AN: 251454 Hom.: 115107 AF XY: 0.957 AC XY: 130010 AN XY: 135902

Gnomad AFR exome AF: 0.971

Gnomad AMR exome AF: 0.965

Gnomad ASJ exome AF: 0.984

Gnomad EAS exome AF: 0.913

Gnomad SAS exome AF: 0.957

Gnomad FIN exome AF: 0.951

Gnomad NFE exome AF: 0.958

Gnomad OTH exome AF: 0.963

GnomAD4 exome AF: 0.954 AC: 1395051 AN: 1461880 Hom.: 665759 Cov.: 76 AF XY: 0.954 AC XY: 694097 AN XY: 727244

Gnomad4 AFR exome AF: 0.969

Gnomad4 AMR exome AF: 0.964

Gnomad4 ASJ exome AF: 0.982

Gnomad4 EAS exome AF: 0.918

Gnomad4 SAS exome AF: 0.957

Gnomad4 FIN exome AF: 0.951

Gnomad4 NFE exome AF: 0.954

Gnomad4 OTH exome AF: 0.955

GnomAD4 genome AF: 0.960 AC: 146191 AN: 152314 Hom.: 70175 Cov.: 32 AF XY: 0.960 AC XY: 71487 AN XY: 74482

Gnomad4 AFR AF: 0.970

Gnomad4 AMR AF: 0.971

Gnomad4 ASJ AF: 0.978

Gnomad4 EAS AF: 0.917

Gnomad4 SAS AF: 0.951

Gnomad4 FIN AF: 0.948

Gnomad4 NFE AF: 0.957

Gnomad4 OTH AF: 0.958

Alfa AF: 0.959 Hom.: 158563

Bravo AF: 0.961

Asia WGS AF: 0.919 AC: 3197 AN: 3478

EpiCase AF: 0.958

EpiControl AF: 0.961

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperglycinuria Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 04, 2021

- -

SLC6A20-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 24, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.34
DANN	Benign	0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs758386; hg19: chr3-45817418;