20-3234173-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_001174089.2(SLC4A11):c.433A>C(p.Arg145=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.418 in 1,613,864 control chromosomes in the GnomAD database, including 145,352 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.49 (18893 hom., cov: 33)
  • Exomes 𝑓: 0.41 (126459 hom.)
• Consequence: SLC4A11 NM_001174089.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 0.824

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 20-3234173-T-G is Benign according to our data. Variant chr20-3234173-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 262001.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=7}.
• BP7: Synonymous conserved (PhyloP=0.824 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.641 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC4A11	NM_001174089.2	c.433A>C	p.Arg145=	synonymous_variant	5/20	ENST00000642402.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC4A11	ENST00000642402.1	c.433A>C	p.Arg145=	synonymous_variant	5/20		NM_001174089.2	P2

Frequencies

GnomAD3 genomes AF: 0.485 AC: 73785 AN: 151990 Hom.: 18868 Cov.: 33

Gnomad AFR AF: 0.647

Gnomad AMI AF: 0.458

Gnomad AMR AF: 0.473

Gnomad ASJ AF: 0.372

Gnomad EAS AF: 0.568

Gnomad SAS AF: 0.330

Gnomad FIN AF: 0.522

Gnomad MID AF: 0.369

Gnomad NFE AF: 0.397

Gnomad OTH AF: 0.442

GnomAD3 exomes AF: 0.438 AC: 109986 AN: 251272 Hom.: 25175 AF XY: 0.426 AC XY: 57926 AN XY: 135834

Gnomad AFR exome AF: 0.655

Gnomad AMR exome AF: 0.464

Gnomad ASJ exome AF: 0.380

Gnomad EAS exome AF: 0.577

Gnomad SAS exome AF: 0.311

Gnomad FIN exome AF: 0.513

Gnomad NFE exome AF: 0.402

Gnomad OTH exome AF: 0.417

GnomAD4 exome AF: 0.411 AC: 600783 AN: 1461756 Hom.: 126459 Cov.: 73 AF XY: 0.408 AC XY: 296498 AN XY: 727168

Gnomad4 AFR exome AF: 0.653

Gnomad4 AMR exome AF: 0.460

Gnomad4 ASJ exome AF: 0.381

Gnomad4 EAS exome AF: 0.548

Gnomad4 SAS exome AF: 0.315

Gnomad4 FIN exome AF: 0.505

Gnomad4 NFE exome AF: 0.400

Gnomad4 OTH exome AF: 0.427

GnomAD4 genome AF: 0.486 AC: 73854 AN: 152108 Hom.: 18893 Cov.: 33 AF XY: 0.489 AC XY: 36336 AN XY: 74362

Gnomad4 AFR AF: 0.647

Gnomad4 AMR AF: 0.472

Gnomad4 ASJ AF: 0.372

Gnomad4 EAS AF: 0.569

Gnomad4 SAS AF: 0.331

Gnomad4 FIN AF: 0.522

Gnomad4 NFE AF: 0.397

Gnomad4 OTH AF: 0.441

Alfa AF: 0.401 Hom.: 14289

Bravo AF: 0.491

Asia WGS AF: 0.411 AC: 1432 AN: 3478

EpiCase AF: 0.386

EpiControl AF: 0.399

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Corneal dystrophy-perceptive deafness syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 19, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Oct 04, 2021	Population allele frequency is 44% (rs3827075, 122,773/276,940 alleles in gnomAD v2.0.2). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as Benign. Following criteria met: BA1 -

Congenital hereditary endothelial dystrophy of cornea Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Uncertain significance, criteria provided, single submitter	case-control	Prof. Brien Holden Eye Research Center, Hyderabad Eye Research Foundation, L V Prasad Eye Institute	Aug 07, 2022	Opaque cornea with reduced visual acuity. This change was observed with the other variant (NM_032034.4:c.[2413_2414insT]). -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2021	- -

Corneal dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	3.5
Dann	Benign	0.45

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: rs3827075; hg19: chr20-3214819; COSMIC: COSV66261640; COSMIC: COSV66261640;