rs386833470

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2PM4_SupportingPP5_Very_Strong

The NM_000111.3(SLC26A3):c.2024_2026dupTCA(p.Ile675dup) variant causes a conservative inframe insertion change. The variant allele was found at a frequency of 0.0000428 in 1,611,250 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

SLC26A3
NM_000111.3 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 3.65

Publications

4 publications found

Variant links:

Genes affected

SLC26A3 (HGNC:3018): (solute carrier family 26 member 3) The protein encoded by this gene is a transmembrane glycoprotein that transports chloride ions across the cell membrane in exchange for bicarbonate ions. It is localized to the mucosa of the lower intestinal tract, particularly to the apical membrane of columnar epithelium and some goblet cells. The protein is essential for intestinal chloride absorption, and mutations in this gene have been associated with congenital chloride diarrhea. [provided by RefSeq, Oct 2008]

SLC26A3 Gene-Disease associations (from GenCC):

congenital secretory chloride diarrhea 1
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, Ambry Genetics

SLC26A3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_000111.3. Strenght limited to Supporting due to length of the change: 1aa.

PP5

Variant 7-107772089-C-CTGA is Pathogenic according to our data. Variant chr7-107772089-C-CTGA is described in ClinVar as [Pathogenic]. Clinvar id is 55988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC26A3	NM_000111.3 link	c.2024_2026dupTCA	p.Ile675dup	conservative_inframe_insertion	Exon 18 of 21	ENST00000340010.10	NP_000102.1	P40879

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC26A3	ENST00000340010.10 link	c.2024_2026dupTCA	p.Ile675dup	conservative_inframe_insertion	Exon 18 of 21	1	NM_000111.3	ENSP00000345873.5	P40879
SLC26A3	ENST00000379083.7 link	n.1581_1583dupTCA		non_coding_transcript_exon_variant	Exon 17 of 20	2		ENSP00000368375.3	F8WBL6
SLC26A3	ENST00000379083.7 link	n.1581_1583dupTCA		3_prime_UTR_variant	Exon 17 of 20	2		ENSP00000368375.3	F8WBL6

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152146

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000598

AC:

AN:

251010

AF XY:

0.0000369

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:

0.0000463

Gnomad NFE exome

AF:

0.000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000411

AC:

AN:

1459104

Hom.:

Cov.:

AF XY:

0.0000386

AC XY:

AN XY:

726042

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33416

American (AMR)

AF:

0.00

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.00

AC:

AN:

39644

South Asian (SAS)

AF:

0.00

AC:

AN:

86202

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53362

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000532

AC:

AN:

1109606

Other (OTH)

AF:

0.00

AC:

AN:

60300

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.443

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41436

American (AMR)

AF:

0.00

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000120

Hom.:

Bravo

AF:

0.0000227

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital secretory diarrhea, chloride type

Pathogenic:5

Apr 15, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

May 28, 2019

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 28, 2008

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Mar 18, 2020

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PS4,PM2,PM3,PM4. This variant was detected in homozygous state. -

not provided

Pathogenic:2

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

- -

Oct 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.2024_2026dup, results in the insertion of 1 amino acid(s) of the SLC26A3 protein (p.Ile675dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs386833470, gnomAD 0.01%). This variant has been observed in individuals with congenital chloride diarrhea (PMID: 9718329, 18216024, 21332001, 28644346). This variant is also known as I675/6ins, c.2025_2026insATC, and I668‚Äì669ins. ClinVar contains an entry for this variant (Variation ID: 55988). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects SLC26A3 function (PMID: 12411484, 18216024). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.6

Mutation Taster

=68/32

disease causing (ClinVar)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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rs386833470

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over