3-45775926-A-G

Variant names:

• chr3-45775926-A-G
• rs758386
• NM_020208.4:c.417T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020208.4(SLC6A20):​c.417T>C​(p.Cys139Cys) 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:5
• Conservation: PhyloP100: -0.325
• Publications: 26 publications found

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]

SLC6A20 Gene-Disease associations (from GenCC):

• hyperglycinuria

  Inheritance: AR, Unknown Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 345420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020208.4. 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
	SLC6A20	NM_020208.4	MANE Select	c.417T>C	p.Cys139Cys	synonymous	Exon 4 of 11	NP_064593.1
	SLC6A20	NM_001385683.1		c.417T>C	p.Cys139Cys	synonymous	Exon 4 of 11	NP_001372612.1
	SLC6A20	NM_022405.4		c.417T>C	p.Cys139Cys	synonymous	Exon 4 of 10	NP_071800.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A20	ENST00000358525.9	TSL:1 MANE Select	c.417T>C	p.Cys139Cys	synonymous	Exon 4 of 11	ENSP00000346298.4
	SLC6A20	ENST00000353278.8	TSL:1	c.417T>C	p.Cys139Cys	synonymous	Exon 4 of 10	ENSP00000296133.5
	SLC6A20	ENST00000703343.1		c.417T>C	p.Cys139Cys	synonymous	Exon 4 of 11	ENSP00000515266.1

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

GnomAD2 exomes AF: 0.957 AC: 240558 AN: 251454 AF XY: 0.957

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 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

African (AFR) AF: 0.969 AC: 32436 AN: 33480

American (AMR) AF: 0.964 AC: 43114 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.982 AC: 25670 AN: 26134

East Asian (EAS) AF: 0.918 AC: 36464 AN: 39700

South Asian (SAS) AF: 0.957 AC: 82550 AN: 86256

European-Finnish (FIN) AF: 0.951 AC: 50800 AN: 53418

Middle Eastern (MID) AF: 0.978 AC: 5642 AN: 5768

European-Non Finnish (NFE) AF: 0.954 AC: 1060727 AN: 1112004

Other (OTH) AF: 0.955 AC: 57648 AN: 60396

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

African (AFR) AF: 0.970 AC: 40282 AN: 41548

American (AMR) AF: 0.971 AC: 14861 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.978 AC: 3397 AN: 3472

East Asian (EAS) AF: 0.917 AC: 4750 AN: 5178

South Asian (SAS) AF: 0.951 AC: 4590 AN: 4824

European-Finnish (FIN) AF: 0.948 AC: 10073 AN: 10626

Middle Eastern (MID) AF: 0.986 AC: 290 AN: 294

European-Non Finnish (NFE) AF: 0.957 AC: 65088 AN: 68038

Other (OTH) AF: 0.958 AC: 2025 AN: 2114

Alfa AF: 0.958 Hom.: 314386

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hyperglycinuria Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SLC6A20-related disorder Benign:1

Sep 24, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.34
DANN	Benign	0.46
PhyloP100		-0.33
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs758386; hg19: chr3-45817418; COSMIC: COSV108191667; COSMIC: COSV108191667;