rs6084312

Positions:

• chr20-3230589-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001174089.2(SLC4A11):​c.1341G>A​(p.Thr447=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 1,613,710 control chromosomes in the GnomAD database, including 9,686 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.085 (718 hom., cov: 34)
  • Exomes 𝑓: 0.11 (8968 hom.)
• Consequence: SLC4A11 NM_001174089.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.197

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 20-3230589-C-T is Benign according to our data. Variant chr20-3230589-C-T is described in ClinVar as [Benign]. Clinvar id is 261996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.197 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC4A11	NM_001174089.2	c.1341G>A	p.Thr447=	synonymous_variant	12/20	ENST00000642402.1	NP_001167560.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC4A11	ENST00000642402.1	c.1341G>A	p.Thr447=	synonymous_variant	12/20		NM_001174089.2	ENSP00000493503	P2

Frequencies

GnomAD3 genomes AF: 0.0848 AC: 12890 AN: 152062 Hom.: 719 Cov.: 34

Gnomad AFR AF: 0.0347

Gnomad AMI AF: 0.0757

Gnomad AMR AF: 0.0863

Gnomad ASJ AF: 0.118

Gnomad EAS AF: 0.00174

Gnomad SAS AF: 0.0219

Gnomad FIN AF: 0.118

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.119

Gnomad OTH AF: 0.0947

GnomAD3 exomes AF: 0.0864 AC: 21720 AN: 251334 Hom.: 1183 AF XY: 0.0859 AC XY: 11677 AN XY: 135874

Gnomad AFR exome AF: 0.0326

Gnomad AMR exome AF: 0.0651

Gnomad ASJ exome AF: 0.125

Gnomad EAS exome AF: 0.00223

Gnomad SAS exome AF: 0.0221

Gnomad FIN exome AF: 0.117

Gnomad NFE exome AF: 0.122

Gnomad OTH exome AF: 0.101

GnomAD4 exome AF: 0.105 AC: 153790 AN: 1461528 Hom.: 8968 Cov.: 48 AF XY: 0.103 AC XY: 74916 AN XY: 727056

Gnomad4 AFR exome AF: 0.0316

Gnomad4 AMR exome AF: 0.0693

Gnomad4 ASJ exome AF: 0.128

Gnomad4 EAS exome AF: 0.00199

Gnomad4 SAS exome AF: 0.0228

Gnomad4 FIN exome AF: 0.111

Gnomad4 NFE exome AF: 0.119

Gnomad4 OTH exome AF: 0.0960

GnomAD4 genome AF: 0.0847 AC: 12886 AN: 152182 Hom.: 718 Cov.: 34 AF XY: 0.0833 AC XY: 6200 AN XY: 74390

Gnomad4 AFR AF: 0.0347

Gnomad4 AMR AF: 0.0862

Gnomad4 ASJ AF: 0.118

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.0222

Gnomad4 FIN AF: 0.118

Gnomad4 NFE AF: 0.119

Gnomad4 OTH AF: 0.0938

Alfa AF: 0.114 Hom.: 1757

Bravo AF: 0.0799

Asia WGS AF: 0.0190 AC: 68 AN: 3478

EpiCase AF: 0.122

EpiControl AF: 0.121

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Corneal dystrophy-perceptive deafness syndrome Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 21, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Corneal dystrophy Benign:1

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

Congenital hereditary endothelial dystrophy of cornea Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.3
DANN	Benign	0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs6084312; hg19: chr20-3211235; COSMIC: COSV66264590; COSMIC: COSV66264590;