1-205917326-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_052934.4(SLC26A9):c.2285A>G(p.Tyr762Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,834 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 (★). Synonymous variant affecting the same amino acid position (i.e. Y762Y) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: SLC26A9 NM_052934.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.300

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07830763).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC26A9	NM_052934.4	c.2285A>G	p.Tyr762Cys	missense_variant	20/21	ENST00000367135.8
SLC26A9	NM_134325.3	c.2285A>G	p.Tyr762Cys	missense_variant	20/22
SLC26A9	XM_011509121.3	c.2018A>G	p.Tyr673Cys	missense_variant	19/20
SLC26A9	XM_011509122.3	c.1793A>G	p.Tyr598Cys	missense_variant	17/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC26A9	ENST00000367135.8	c.2285A>G	p.Tyr762Cys	missense_variant	20/21	1	NM_052934.4	P1
SLC26A9	ENST00000340781.8	c.2285A>G	p.Tyr762Cys	missense_variant	19/21	1
SLC26A9	ENST00000367134.2	c.2285A>G	p.Tyr762Cys	missense_variant	20/22	5
SLC26A9	ENST00000491127.5	n.1669A>G		non_coding_transcript_exon_variant	12/13	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251416 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135876

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461834 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727224

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000312 Hom.: 0

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

Jul 26, 2022

The c.2285A>G (p.Y762C) alteration is located in exon 20 (coding exon 19) of the SLC26A9 gene. This alteration results from a A to G substitution at nucleotide position 2285, causing the tyrosine (Y) at amino acid position 762 to be replaced by a cysteine (C). 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	0.061
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	11
Dann	Benign	0.92
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.039	N
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.078	T;T;T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	0.34	N;N;N
MutationTaster	Benign	0.99	N;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.72	N;N;N
REVEL	Benign	0.13
Sift	Benign	0.11	T;T;T
Sift4G	Benign	0.15	T;T;T
Polyphen		0.0	.;B;.
Vest4		0.32
MutPred		0.36		Loss of phosphorylation at Y762 (P = 0.0193);Loss of phosphorylation at Y762 (P = 0.0193);Loss of phosphorylation at Y762 (P = 0.0193);
MVP		0.23
MPC		0.17
ClinPred		0.051	T
GERP RS		0.21
Varity_R		0.077
gMVP		0.40

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: rs1445687345; hg19: chr1-205886454;