7-107791226-G-C

Position:

• chr7-107791226-G-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

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 Conflicting classifications of pathogenicity (no stars). 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: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 8.94

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a transmembrane_region Helical (size 20) in uniprot entity S26A3_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) 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 Lovd as [Likely_pathogenic].
• 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 ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 55999.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}. Variant chr7-107791226-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC26A3	NM_000111.3	c.392C>G	p.Pro131Arg	missense_variant	5/21	ENST00000340010.10	NP_000102.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC26A3	ENST00000340010.10	c.392C>G	p.Pro131Arg	missense_variant	5/21	1	NM_000111.3	ENSP00000345873	P1
SLC26A3	ENST00000379083.7	c.*183C>G		3_prime_UTR_variant, NMD_transcript_variant	5/20	2		ENSP00000368375

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251430 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135874

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: 0.0000352

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

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: 0.0000396

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Congenital secretory diarrhea, chloride type Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	The SLC26A3 c.392C>G (p.Pro131Arg) variant is a missense variant that has been reported in two studies in a total of three unrelated individuals with familial chloride diarrhea, including one in a compound heterozygous state and two in a heterozygous state (Hoglund et al. 1998; Pieroni and Bass 2011). One of the individuals who was heterozygous for the variant was also heterozygous for a frameshift variant, although the phase of these variants is not reported. The p.Pro131Arg variant was absent from 104 control chromosomes and is reported at a frequency of 0.00002 in the European (non-Finnish) population of the Exome Aggregation Consortium. This frequency is based on one allele in an area of good coverage, so the variant is presumed to be rare. Based on the evidence, the p.Pro131Arg variant is classified as a variant of unknown significance but suspicious for pathogenicity for familial chloride diarrhea. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely pathogenic, no assertion criteria provided	literature only	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	-	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 04, 2024

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
MutationTaster	Benign	1.0	D;D
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

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: rs386833481; hg19: chr7-107431671;