NM_001174089.2:c.2480T>C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP3_StrongPP5_Very_Strong

The NM_001174089.2(SLC4A11):c.2480T>C(p.Leu827Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000446 in 1,612,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L827L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

SLC4A11
NM_001174089.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 7.44

Publications

11 publications found

Variant links:

Genes affected

SLC4A11 (HGNC:16438): (solute carrier family 4 member 11) This gene encodes a voltage-regulated, electrogenic sodium-coupled borate cotransporter that is essential for borate homeostasis, cell growth and cell proliferation. Mutations in this gene have been associated with a number of endothelial corneal dystrophies including recessive corneal endothelial dystrophy 2, corneal dystrophy and perceptive deafness, and Fuchs endothelial corneal dystrophy. Multiple transcript variants encoding different isoforms have been described. [provided by RefSeq, Mar 2010]

SLC4A11 Gene-Disease associations (from GenCC):

corneal dystrophy, Fuchs endothelial, 4
Inheritance: AD Classification: STRONG, LIMITED Submitted by: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
congenital hereditary endothelial dystrophy of cornea
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet
corneal dystrophy-perceptive deafness syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
Fuchs' endothelial dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SLC4A11 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.979

PP5

Variant 20-3228337-A-G is Pathogenic according to our data. Variant chr20-3228337-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001174089.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC4A11	NM_001174089.2	MANE Select	c.2480T>C	p.Leu827Pro	missense	Exon 19 of 20	NP_001167560.1	Q8NBS3-3
SLC4A11	NM_001174090.2		c.2609T>C	p.Leu870Pro	missense	Exon 19 of 20	NP_001167561.1	Q8NBS3-4
SLC4A11	NM_032034.4		c.2528T>C	p.Leu843Pro	missense	Exon 18 of 19	NP_114423.1	Q8NBS3-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC4A11	ENST00000642402.1	MANE Select	c.2480T>C	p.Leu827Pro	missense	Exon 19 of 20	ENSP00000493503.1	Q8NBS3-3
SLC4A11	ENST00000380056.7	TSL:1	c.2528T>C	p.Leu843Pro	missense	Exon 18 of 19	ENSP00000369396.3	Q8NBS3-1
SLC4A11	ENST00000380059.7	TSL:2	c.2609T>C	p.Leu870Pro	missense	Exon 19 of 20	ENSP00000369399.3	Q8NBS3-4

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152058

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000159

AC:

AN:

251080

AF XY:

0.0000294

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000445

AC:

AN:

1460886

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

726780

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33458

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.0000190

AC:

AN:

52628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000558

AC:

AN:

1111862

Other (OTH)

AF:

0.0000331

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152058

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74274

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41422

American (AMR)

AF:

0.00

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

67994

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000916

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Corneal dystrophy-perceptive deafness syndrome (3)

not provided (3)

Congenital hereditary endothelial dystrophy of cornea (1)

Congenital hereditary endothelial dystrophy of cornea;C1857572:Corneal dystrophy-perceptive deafness syndrome;C2750450:Corneal dystrophy, Fuchs endothelial, 4 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.72

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.55

MetaRNN

Pathogenic

0.98

MetaSVM

Uncertain

0.70

MutationAssessor

Uncertain

2.7

PhyloP100

7.4

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-6.1

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

0.34

Vest4

0.93

MutPred

0.89

Gain of catalytic residue at L843 (P = 0.007)

MVP

0.94

MPC

0.86

ClinPred

0.98

GERP RS

5.4

Varity_R

0.93

gMVP

0.99

Mutation Taster

=1/99

disease causing (ClinVar)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over