1-205918920-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_052934.4(SLC26A9):c.2176G>A(p.Val726Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000923 in 1,614,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000092 (0 hom.)
• Consequence: SLC26A9 NM_052934.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.563

Genes affected

SLC26A9 (HGNC:14469): (solute carrier family 26 member 9) This gene is one member of a family of sulfate/anion transporter genes. Family members are well conserved in their genomic (number and size of exons) and protein (aa length among species) structures yet have markedly different tissue expression patterns. The product of this gene is a highly selective chloride ion channel regulated by WNK kinases. Alternative splicing results in multiple transcript variants encoding differing isoforms.[provided by RefSeq, Dec 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0582411).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC26A9	NM_052934.4	c.2176G>A	p.Val726Ile	missense_variant	19/21	ENST00000367135.8
SLC26A9	NM_134325.3	c.2176G>A	p.Val726Ile	missense_variant	19/22
SLC26A9	XM_011509121.3	c.1909G>A	p.Val637Ile	missense_variant	18/20
SLC26A9	XM_011509122.3	c.1684G>A	p.Val562Ile	missense_variant	16/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC26A9	ENST00000367135.8	c.2176G>A	p.Val726Ile	missense_variant	19/21	1	NM_052934.4	P1
SLC26A9	ENST00000340781.8	c.2176G>A	p.Val726Ile	missense_variant	18/21	1
SLC26A9	ENST00000367134.2	c.2176G>A	p.Val726Ile	missense_variant	19/22	5
SLC26A9	ENST00000491127.5	n.1560G>A		non_coding_transcript_exon_variant	11/13	2

Frequencies

GnomAD3 genomes AF: 0.0000985 AC: 15 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000139 AC: 35 AN: 251472 Hom.: 0 AF XY: 0.000132 AC XY: 18 AN XY: 135908

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.000149

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000917 AC: 134 AN: 1461880 Hom.: 0 Cov.: 31 AF XY: 0.000102 AC XY: 74 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.000344

Gnomad4 EAS exome AF: 0.000302

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.000655

Gnomad4 NFE exome AF: 0.0000612

Gnomad4 OTH exome AF: 0.0000993

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152222 Hom.: 0 Cov.: 33 AF XY: 0.0000941 AC XY: 7 AN XY: 74368

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000376

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000143 Hom.: 0

Bravo AF: 0.0000793

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000198 AC: 24

EpiCase AF: 0.000382

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 17, 2023

The c.2176G>A (p.V726I) alteration is located in exon 19 (coding exon 18) of the SLC26A9 gene. This alteration results from a G to A substitution at nucleotide position 2176, causing the valine (V) at amino acid position 726 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	8.4
Dann	Benign	0.96
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.54	D
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.058	T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	-0.52	N;N;N
MutationTaster	Benign	0.93	N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.61	N;N;N
REVEL	Benign	0.13
Sift	Benign	0.19	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0010	.;B;.
Vest4		0.054
MVP		0.34
MPC		0.11
ClinPred		0.062	T
GERP RS		-0.39
Varity_R		0.085
gMVP		0.12

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: rs139528306; hg19: chr1-205888048;