1-205915365-C-T

Variant names:

• chr1-205915365-C-T
• rs769077038
• NM_052934.4:c.2368G>A

Variant summary

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

The NM_052934.4(SLC26A9):​c.2368G>A​(p.Ala790Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000397 in 1,614,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A790S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: SLC26A9 NM_052934.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.20

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=0.26178688).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC26A9	NM_052934.4	c.2368G>A	p.Ala790Thr	missense_variant	Exon 21 of 21	ENST00000367135.8	NP_443166.1
SLC26A9	NM_134325.3	c.2368G>A	p.Ala790Thr	missense_variant	Exon 21 of 22		NP_599152.2
SLC26A9	XM_011509121.3	c.2101G>A	p.Ala701Thr	missense_variant	Exon 20 of 20		XP_011507423.1
SLC26A9	XM_011509122.3	c.1876G>A	p.Ala626Thr	missense_variant	Exon 18 of 18		XP_011507424.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC26A9	ENST00000367135.8	c.2368G>A	p.Ala790Thr	missense_variant	Exon 21 of 21	1	NM_052934.4	ENSP00000356103.3
SLC26A9	ENST00000340781.8	c.2368G>A	p.Ala790Thr	missense_variant	Exon 20 of 21	1		ENSP00000341682.4
SLC26A9	ENST00000367134.2	c.2368G>A	p.Ala790Thr	missense_variant	Exon 21 of 22	5		ENSP00000356102.2
SLC26A9	ENST00000491127.5	n.1752G>A		non_coding_transcript_exon_variant	Exon 13 of 13	2

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000485 AC: 12 AN: 247616 Hom.: 0 AF XY: 0.0000522 AC XY: 7 AN XY: 134048

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000908

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.0000383 AC: 56 AN: 1461822 Hom.: 0 Cov.: 32 AF XY: 0.0000481 AC XY: 35 AN XY: 727220

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000453

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74352

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.0000330 AC: 4

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2368G>A (p.A790T) alteration is located in exon 21 (coding exon 20) of the SLC26A9 gene. This alteration results from a G to A substitution at nucleotide position 2368, causing the alanine (A) at amino acid position 790 to be replaced by a threonine (T). 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	0.13
BayesDel_addAF	Benign	-0.0016	T
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.055	.;T;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.54	.;T;T
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Uncertain	0.73	D
MutationAssessor	Benign	0.90	L;L;L
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.59	N;N;N
REVEL	Uncertain	0.37
Sift	Uncertain	0.0060	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.64
MVP		0.58
MPC		0.51
ClinPred		0.27	T
GERP RS		5.4
Varity_R		0.22
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs769077038; hg19: chr1-205884493; COSMIC: COSV61601433;