1-205915098-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The ENST00000340781.8(SLC26A9):c.2458G>A(p.Ala820Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,613,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: SLC26A9 ENST00000340781.8 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.24

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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.045147628).
• BP6: Variant 1-205915098-C-T is Benign according to our data. Variant chr1-205915098-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2511496.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC26A9	NM_052934.4	c.*259G>A		3_prime_UTR_variant	21/21	ENST00000367135.8
SLC26A9	NM_134325.3	c.2458G>A	p.Ala820Thr	missense_variant	22/22
SLC26A9	XM_011509121.3	c.*259G>A		3_prime_UTR_variant	20/20
SLC26A9	XM_011509122.3	c.*259G>A		3_prime_UTR_variant	18/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC26A9	ENST00000340781.8	c.2458G>A	p.Ala820Thr	missense_variant	21/21	1
SLC26A9	ENST00000367135.8	c.*259G>A		3_prime_UTR_variant	21/21	1	NM_052934.4	P1
SLC26A9	ENST00000367134.2	c.2458G>A	p.Ala820Thr	missense_variant	22/22	5
SLC26A9	ENST00000491127.5	n.2019G>A		non_coding_transcript_exon_variant	13/13	2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 250714 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135454

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1461670 Hom.: 0 Cov.: 32 AF XY: 0.0000193 AC XY: 14 AN XY: 727120

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152276 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74446

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000453

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 13, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	0.077
Dann	Benign	0.66
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0017	N
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.045	T;T
MetaSVM	Benign	-0.38	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.020	N;N
REVEL	Benign	0.24
Sift	Benign	0.081	T;T
Sift4G	Benign	0.59	T;T
Vest4		0.016
MutPred		0.16		Gain of glycosylation at A820 (P = 0.0131);Gain of glycosylation at A820 (P = 0.0131);
MVP		0.088
MPC		0.13
ClinPred		0.039	T
GERP RS		-6.2
gMVP		0.030

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: rs34309781; hg19: chr1-205884226;