rs61733910

chr22-32110064-G-Achr22-32110064-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PM2 PP2 BP4_Strong BP6 BS1

The NM_000343.4(SLC5A1):c.1846G>A(p.Gly616Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,613,984 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00078 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (0 hom.)
• Consequence: SLC5A1 NM_000343.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 2.49

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]

LOC105373000 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SLC5A1
• BP4: Computational evidence support a benign effect (MetaRNN=0.01036337).
• BP6: Variant 22-32110064-G-A is Benign according to our data. Variant chr22-32110064-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 341264.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}. Variant chr22-32110064-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000775 (118/152214) while in subpopulation NFE AF= 0.00138 (94/68010). AF 95% confidence interval is 0.00116. There are 0 homozygotes in gnomad4. There are 52 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC5A1	NM_000343.4	c.1846G>A	p.Gly616Ser	missense_variant	15/15	ENST00000266088.9
LOC105373000	XR_938172.3	n.408-3122C>T		intron_variant, non_coding_transcript_variant
SLC5A1	NM_001256314.2	c.1465G>A	p.Gly489Ser	missense_variant	14/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC5A1	ENST00000266088.9	c.1846G>A	p.Gly616Ser	missense_variant	15/15	1	NM_000343.4	P1
SLC5A1	ENST00000543737.2	c.1465G>A	p.Gly489Ser	missense_variant	14/14	2

Frequencies

GnomAD3 genomes AF: 0.000782 AC: 119 AN: 152096 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00125

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00138

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00142 AC: 357 AN: 251426 Hom.: 0 AF XY: 0.00160 AC XY: 218 AN XY: 135878

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00140

Gnomad FIN exome AF: 0.000970

Gnomad NFE exome AF: 0.00241

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00146 AC: 2137 AN: 1461770 Hom.: 0 Cov.: 31 AF XY: 0.00145 AC XY: 1057 AN XY: 727192

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00138

Gnomad4 FIN exome AF: 0.00124

Gnomad4 NFE exome AF: 0.00167

Gnomad4 OTH exome AF: 0.00121

GnomAD4 genome AF: 0.000775 AC: 118 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.000699 AC XY: 52 AN XY: 74432

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00138

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00140 Hom.: 0

Bravo AF: 0.000699

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.00204 AC: 248

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00153

EpiControl AF: 0.00148

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Congenital glucose-galactose malabsorption Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Jul 12, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	8.7
Dann	Benign	0.42
DEOGEN2	Benign	0.043	T;.
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.22	T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.010	T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	-0.47	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.27	N;N
REVEL	Benign	0.13
Sift	Benign	0.25	T;T
Sift4G	Benign	0.78	T;T
Polyphen		0.0	B;.
Vest4		0.030
MVP		0.76
MPC		0.46
ClinPred		0.011	T
GERP RS		4.5
Varity_R		0.034
gMVP		0.22

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: rs61733910; hg19: chr22-32506051;