rs121909391

Variant names:

• chr20-3228260-G-A
• rs121909391
• NM_001174089.2:c.2557C>T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_001174089.2(SLC4A11):​c.2557C>T​(p.Arg853Cys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000206 in 1,459,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R853H) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SLC4A11 NM_001174089.2 missense, splice_region
• Scores: Splicing: ADA: 0.1059
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 4.75

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a transmembrane_region Helical (size 20) in uniprot entity S4A11_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_001174089.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr20-3228259-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 20-3228260-G-A is Pathogenic according to our data. Variant chr20-3228260-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1309.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr20-3228260-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC4A11	NM_001174089.2	c.2557C>T	p.Arg853Cys	missense_variant, splice_region_variant	Exon 19 of 20	ENST00000642402.1	NP_001167560.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC4A11	ENST00000642402.1	c.2557C>T	p.Arg853Cys	missense_variant, splice_region_variant	Exon 19 of 20		NM_001174089.2	ENSP00000493503.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD3 exomes AF: 0.00000801 AC: 2 AN: 249842 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135536

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459058 Hom.: 0 Cov.: 36 AF XY: 0.00000413 AC XY: 3 AN XY: 725796

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

Alfa AF: 0.000138 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital hereditary endothelial dystrophy of cornea Pathogenic:2

Mar 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 07, 2022

Prof. Brien Holden Eye Research Center, Hyderabad Eye Research Foundation, L V Prasad Eye Institute

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: case-control

Opaque cornea with reduced visual acuity -

not provided Pathogenic:1

Sep 15, 2021

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;.;.;.;.;.;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D;D;.;D;D;D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Uncertain	2.5	M;.;.;.;.;.;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-7.3	D;D;.;.;.;.;D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;D;.;.;.;.;D
Sift4G	Pathogenic	0.0	D;D;.;.;.;.;D
Polyphen		1.0	D;.;.;.;.;.;.
Vest4		0.95
MutPred		0.96		Gain of helix (P = 0.0496);.;.;.;.;.;.;
MVP		0.97
MPC		1.1
ClinPred		0.99	D
GERP RS		3.2
Varity_R		0.81
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.11
dbscSNV1_RF	Benign	0.38
SpliceAI score (max)		0.010		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: rs121909391; hg19: chr20-3208906;