chr22-32110063-C-G

Variant names:

• chr22-32110063-C-G
• rs33954001
• NM_000343.4:c.1845C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000343.4(SLC5A1):​c.1845C>G​(p.His615Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0655 in 1,613,006 control chromosomes in the GnomAD database, including 3,936 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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. H615H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.045 (206 hom., cov: 32)
  • Exomes 𝑓: 0.068 (3730 hom.)
• Consequence: SLC5A1 NM_000343.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.134
• Publications: 21 publications found

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]

SLC5A1 Gene-Disease associations (from GenCC):

• glucose-galactose malabsorption

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)

LOC105373000 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018596649).
• BP6: Variant 22-32110063-C-G is Benign according to our data. Variant chr22-32110063-C-G is described in ClinVar as Benign. ClinVar VariationId is 341263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0689 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC5A1	NM_000343.4	c.1845C>G	p.His615Gln	missense_variant	Exon 15 of 15	ENST00000266088.9	NP_000334.1
SLC5A1	NM_001256314.2	c.1464C>G	p.His488Gln	missense_variant	Exon 14 of 14		NP_001243243.1
LOC105373000	XR_938172.3	n.408-3121G>C		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC5A1	ENST00000266088.9	c.1845C>G	p.His615Gln	missense_variant	Exon 15 of 15	1	NM_000343.4	ENSP00000266088.4
SLC5A1	ENST00000543737.2	c.1464C>G	p.His488Gln	missense_variant	Exon 14 of 14	2		ENSP00000444898.1

Frequencies

GnomAD3 genomes AF: 0.0450 AC: 6850 AN: 152090 Hom.: 207 Cov.: 32

Gnomad AFR AF: 0.0124

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0344

Gnomad ASJ AF: 0.0412

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0374

Gnomad FIN AF: 0.0557

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0706

Gnomad OTH AF: 0.0369

GnomAD2 exomes AF: 0.0485 AC: 12189 AN: 251408 AF XY: 0.0495

Gnomad AFR exome AF: 0.0115

Gnomad AMR exome AF: 0.0292

Gnomad ASJ exome AF: 0.0382

Gnomad EAS exome AF: 0.00125

Gnomad FIN exome AF: 0.0516

Gnomad NFE exome AF: 0.0703

Gnomad OTH exome AF: 0.0451

GnomAD4 exome AF: 0.0676 AC: 98770 AN: 1460798 Hom.: 3730 Cov.: 31 AF XY: 0.0668 AC XY: 48572 AN XY: 726754

African (AFR) AF: 0.00986 AC: 330 AN: 33468

American (AMR) AF: 0.0319 AC: 1425 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0408 AC: 1067 AN: 26132

East Asian (EAS) AF: 0.00184 AC: 73 AN: 39700

South Asian (SAS) AF: 0.0423 AC: 3652 AN: 86244

European-Finnish (FIN) AF: 0.0565 AC: 3020 AN: 53420

Middle Eastern (MID) AF: 0.0317 AC: 183 AN: 5766

European-Non Finnish (NFE) AF: 0.0770 AC: 85525 AN: 1110990

Other (OTH) AF: 0.0579 AC: 3495 AN: 60360

GnomAD4 genome AF: 0.0450 AC: 6851 AN: 152208 Hom.: 206 Cov.: 32 AF XY: 0.0435 AC XY: 3234 AN XY: 74414

African (AFR) AF: 0.0123 AC: 512 AN: 41508

American (AMR) AF: 0.0346 AC: 530 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0412 AC: 143 AN: 3472

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5188

South Asian (SAS) AF: 0.0378 AC: 182 AN: 4814

European-Finnish (FIN) AF: 0.0557 AC: 591 AN: 10606

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0706 AC: 4798 AN: 68008

Other (OTH) AF: 0.0365 AC: 77 AN: 2110

Alfa AF: 0.0538 Hom.: 154

Bravo AF: 0.0428

TwinsUK AF: 0.0747 AC: 277

ALSPAC AF: 0.0810 AC: 312

ESP6500AA AF: 0.0138 AC: 61

ESP6500EA AF: 0.0699 AC: 601

ExAC AF: 0.0500 AC: 6073

EpiCase AF: 0.0603

EpiControl AF: 0.0659

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital glucose-galactose malabsorption Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 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. -

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	6.8
DANN	Benign	0.28
DEOGEN2	Benign	0.041	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.010	T;T
MetaRNN	Benign	0.0019	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-2.0	N;.
PhyloP100		0.13
PrimateAI	Benign	0.31	T
PROVEAN	Benign	1.4	N;N
REVEL	Benign	0.21
Sift	Benign	0.65	T;T
Sift4G	Benign	0.79	T;T
Polyphen		0.0	B;.
Vest4		0.012
MutPred		0.41		Gain of loop (P = 0.1081);.;
MPC		0.47
ClinPred		0.0016	T
GERP RS		2.9
Varity_R		0.040
gMVP		0.14
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs33954001; hg19: chr22-32506050;