Genetic Variant SLC26A3:p.Cys343Ser (chr7-107783296-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 6P and 2B. PM1PM2PM5BP4_Moderate

The NM_000111.3(SLC26A3):c.1028G>C(p.Cys343Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C343Y) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SLC26A3
NM_000111.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.01

Publications

1 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: Uncertain_significance. The variant received 4 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 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 chr7-107783296-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 55962.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.20931974).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC26A3	NM_000111.3 link	c.1028G>C	p.Cys343Ser	missense_variant	Exon 9 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.1028G>C	p.Cys343Ser	missense_variant	Exon 9 of 21	1	NM_000111.3	ENSP00000345873.5	P40879
SLC26A3	ENST00000379083.7 link	n.*819G>C		non_coding_transcript_exon_variant	Exon 9 of 20	2		ENSP00000368375.3	F8WBL6
SLC26A3	ENST00000468551.1 link	n.306G>C		non_coding_transcript_exon_variant	Exon 3 of 5	2
SLC26A3	ENST00000379083.7 link	n.*819G>C		3_prime_UTR_variant	Exon 9 of 20	2		ENSP00000368375.3	F8WBL6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111996

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.034

BayesDel_noAF

Benign

-0.29

CADD

Benign

9.9

(source)

DANN

Benign

0.46

DEOGEN2

Benign

0.33

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.51

M_CAP

Benign

0.016

MetaRNN

Benign

0.21

MetaSVM

Benign

-0.54

MutationAssessor

Benign

-0.42

PhyloP100

2.0

PrimateAI

Benign

0.29

PROVEAN

Benign

1.0

REVEL

Benign

0.28

Sift

Benign

0.41

Sift4G

Benign

0.43

Polyphen

0.0010

Vest4

0.21

MutPred

0.85

Gain of disorder (P = 0.1151);

MVP

0.76

MPC

0.21

ClinPred

0.10

GERP RS

4.3

Varity_R

0.17

gMVP

0.76

Mutation Taster

=50/50

(source)

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

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chr7-107783296-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over