7-107791226-G-C

Variant names:

• chr7-107791226-G-C
• rs386833481
• NM_000111.3:c.392C>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000111.3(SLC26A3):​c.392C>G​(p.Pro131Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000301 in 1,461,876 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P131L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: SLC26A3 NM_000111.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.94
• Publications: 11 publications found

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

ACMG classification

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

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000111.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-107791226-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 56000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 7-107791226-G-C is Pathogenic according to our data. Variant chr7-107791226-G-C is described in CliVar as Pathogenic. Clinvar id is 55999.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-107791226-G-C is described in CliVar as Pathogenic. Clinvar id is 55999.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-107791226-G-C is described in CliVar as Pathogenic. Clinvar id is 55999.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-107791226-G-C is described in CliVar as Pathogenic. Clinvar id is 55999.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-107791226-G-C is described in CliVar as Pathogenic. Clinvar id is 55999.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-107791226-G-C is described in CliVar as Pathogenic. Clinvar id is 55999.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-107791226-G-C is described in CliVar as Pathogenic. Clinvar id is 55999.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-107791226-G-C is described in CliVar as Pathogenic. Clinvar id is 55999.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-107791226-G-C is described in CliVar as Pathogenic. Clinvar id is 55999.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-107791226-G-C is described in CliVar as Pathogenic. Clinvar id is 55999.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-107791226-G-C is described in CliVar as Pathogenic. Clinvar id is 55999.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-107791226-G-C is described in CliVar as Pathogenic. Clinvar id is 55999.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-107791226-G-C is described in CliVar as Pathogenic. Clinvar id is 55999.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-107791226-G-C is described in CliVar as Pathogenic. Clinvar id is 55999.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-107791226-G-C is described in CliVar as Pathogenic. Clinvar id is 55999.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-107791226-G-C is described in CliVar as Pathogenic. Clinvar id is 55999.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-107791226-G-C is described in CliVar as Pathogenic. Clinvar id is 55999.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-107791226-G-C is described in CliVar as Pathogenic. Clinvar id is 55999.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-107791226-G-C is described in CliVar as Pathogenic. Clinvar id is 55999.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-107791226-G-C is described in CliVar as Pathogenic. Clinvar id is 55999.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-107791226-G-C is described in CliVar as Pathogenic. Clinvar id is 55999.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-107791226-G-C is described in CliVar as Pathogenic. Clinvar id is 55999.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-107791226-G-C is described in CliVar as Pathogenic. Clinvar id is 55999.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-107791226-G-C is described in CliVar as Pathogenic. Clinvar id is 55999.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-107791226-G-C is described in CliVar as Pathogenic. Clinvar id is 55999.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC26A3	NM_000111.3	c.392C>G	p.Pro131Arg	missense_variant	Exon 5 of 21	ENST00000340010.10	NP_000102.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC26A3	ENST00000340010.10	c.392C>G	p.Pro131Arg	missense_variant	Exon 5 of 21	1	NM_000111.3	ENSP00000345873.5
SLC26A3	ENST00000379083.7	n.*183C>G		non_coding_transcript_exon_variant	Exon 5 of 20	2		ENSP00000368375.3
SLC26A3	ENST00000379083.7	n.*183C>G		3_prime_UTR_variant	Exon 5 of 20	2		ENSP00000368375.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251430 AF XY: 0.0000147

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: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000301 AC: 44 AN: 1461876 Hom.: 0 Cov.: 32 AF XY: 0.0000234 AC XY: 17 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000396 AC: 44 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital secretory diarrhea, chloride type Pathogenic:1

-

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

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Jan 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 131 of the SLC26A3 protein (p.Pro131Arg). This variant is present in population databases (rs386833481, gnomAD 0.004%). This missense change has been observed in individual(s) with congenital secretory chloride diarrhea (PMID: 9554749, 28644346). ClinVar contains an entry for this variant (Variation ID: 55999). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC26A3 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SLC26A3 function (PMID: 31114672). This variant disrupts the p.Pro131 amino acid residue in SLC26A3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23274434, 25711268). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		8.9
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-7.3	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.93		Gain of catalytic residue at P131 (P = 0.0327);
MVP		1.0
MPC		0.72
ClinPred		0.91	D
GERP RS		5.7
Varity_R		0.98
gMVP		0.93
Mutation Taster		=4/96	disease causing

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

Other links and lift over

dbSNP: rs386833481; hg19: chr7-107431671;