rs17683011

chr22-32049959-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000343.4(SLC5A1):c.152A>G(p.Asn51Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0653 in 1,613,218 control chromosomes in the GnomAD database, including 3,926 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. N51N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.045 (208 hom., cov: 31)
  • Exomes 𝑓: 0.067 (3718 hom.)
• Consequence: SLC5A1 NM_000343.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.42

Genes affected

SLC5A1 (HGNC:11036): (solute carrier family 5 member 1) This gene encodes a member of the sodium-dependent glucose transporter (SGLT) family. The encoded integral membrane protein is the primary mediator of dietary glucose and galactose uptake from the intestinal lumen. Mutations in this gene have been associated with glucose-galactose malabsorption. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SLC5A1
• BP4: Computational evidence support a benign effect (MetaRNN=0.0032442808).
• BP6: Variant 22-32049959-A-G is Benign according to our data. Variant chr22-32049959-A-G is described in ClinVar as [Benign]. Clinvar id is 341236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0688 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC5A1	NM_000343.4	c.152A>G	p.Asn51Ser	missense_variant	2/15	ENST00000266088.9
SLC5A1	XM_011530331.2	c.152A>G	p.Asn51Ser	missense_variant	2/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC5A1	ENST00000266088.9	c.152A>G	p.Asn51Ser	missense_variant	2/15	1	NM_000343.4	P1

Frequencies

GnomAD3 genomes AF: 0.0449 AC: 6824 AN: 152080 Hom.: 209 Cov.: 31

Gnomad AFR AF: 0.0124

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0346

Gnomad ASJ AF: 0.0412

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0332

Gnomad FIN AF: 0.0558

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0704

Gnomad OTH AF: 0.0368

GnomAD3 exomes AF: 0.0480 AC: 12081 AN: 251482 Hom.: 373 AF XY: 0.0489 AC XY: 6646 AN XY: 135914

Gnomad AFR exome AF: 0.0115

Gnomad AMR exome AF: 0.0296

Gnomad ASJ exome AF: 0.0382

Gnomad EAS exome AF: 0.00130

Gnomad SAS exome AF: 0.0342

Gnomad FIN exome AF: 0.0517

Gnomad NFE exome AF: 0.0704

Gnomad OTH exome AF: 0.0456

GnomAD4 exome AF: 0.0675 AC: 98553 AN: 1461020 Hom.: 3718 Cov.: 32 AF XY: 0.0665 AC XY: 48339 AN XY: 726834

Gnomad4 AFR exome AF: 0.00992

Gnomad4 AMR exome AF: 0.0323

Gnomad4 ASJ exome AF: 0.0407

Gnomad4 EAS exome AF: 0.00184

Gnomad4 SAS exome AF: 0.0375

Gnomad4 FIN exome AF: 0.0566

Gnomad4 NFE exome AF: 0.0771

Gnomad4 OTH exome AF: 0.0579

GnomAD4 genome AF: 0.0448 AC: 6825 AN: 152198 Hom.: 208 Cov.: 31 AF XY: 0.0432 AC XY: 3214 AN XY: 74394

Gnomad4 AFR AF: 0.0123

Gnomad4 AMR AF: 0.0349

Gnomad4 ASJ AF: 0.0412

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0336

Gnomad4 FIN AF: 0.0558

Gnomad4 NFE AF: 0.0704

Gnomad4 OTH AF: 0.0364

Alfa AF: 0.0594 Hom.: 565

Bravo AF: 0.0427

TwinsUK AF: 0.0752 AC: 279

ALSPAC AF: 0.0807 AC: 311

ESP6500AA AF: 0.0138 AC: 61

ESP6500EA AF: 0.0701 AC: 603

ExAC AF: 0.0495 AC: 6005

Asia WGS AF: 0.0200 AC: 69 AN: 3478

EpiCase AF: 0.0604

EpiControl AF: 0.0660

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital glucose-galactose malabsorption Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	21
Dann	Benign	0.95
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	0.98	D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.29
Sift	Benign	0.33	T
Sift4G	Benign	0.43	T
Polyphen		0.13	B
Vest4		0.16
MPC		0.37
ClinPred		0.031	T
GERP RS		3.4
Varity_R		0.18
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs17683011; hg19: chr22-32445946; COSMIC: COSV56682930;