dbSNP rs121908323: SLC2A9:p.Pro412Leu (chr4-9887623-G-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PM5

The NM_020041.3(SLC2A9):c.1235C>T(p.Pro412Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000712 in 1,403,960 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P412R) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

SLC2A9
NM_020041.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.40

Publications

0 publications found

Variant links:

Genes affected

SLC2A9 (HGNC:13446): (solute carrier family 2 member 9) This gene encodes a member of the SLC2A facilitative glucose transporter family. Members of this family play a significant role in maintaining glucose homeostasis. The encoded protein may play a role in the development and survival of chondrocytes in cartilage matrices. Two transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

SLC2A9 Gene-Disease associations (from GenCC):

hypouricemia, renal, 2
Inheritance: AD, AR Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
hereditary renal hypouricemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SLC2A9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr4-9887623-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 4598.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC2A9	NM_020041.3 link	c.1235C>T	p.Pro412Leu	missense_variant	Exon 10 of 12	ENST00000264784.8	NP_064425.2	Q9NRM0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC2A9	ENST00000264784.8 link	c.1235C>T	p.Pro412Leu	missense_variant	Exon 10 of 12	1	NM_020041.3	ENSP00000264784.3		Q9NRM0-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.12e-7

AC:

AN:

1403960

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

692382

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32038

American (AMR)

AF:

0.00

AC:

AN:

38348

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24156

East Asian (EAS)

AF:

0.00

AC:

AN:

36682

South Asian (SAS)

AF:

0.0000129

AC:

AN:

77268

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50474

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5620

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1081384

Other (OTH)

AF:

0.00

AC:

AN:

57990

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.030

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

T;.;.

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.89

D;.;D

M_CAP

Benign

0.051

MetaRNN

Uncertain

0.70

D;D;D

MetaSVM

Uncertain

-0.14

MutationAssessor

Uncertain

2.8

M;.;.

PhyloP100

3.4

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-6.7

D;D;D

REVEL

Uncertain

0.30

Sift

Uncertain

0.0060

D;D;D

Sift4G

Benign

0.20

T;T;T

Polyphen

0.36

B;B;B

Vest4

0.78

MutPred

0.65

Loss of helix (P = 0.1706);.;.;

MVP

0.78

MPC

0.52

ClinPred

0.99

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.52

gMVP

0.91

Mutation Taster

=34/66

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over