1-205918853-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_052934.4(SLC26A9):c.2243A>G(p.His748Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0788 in 1,612,986 control chromosomes in the GnomAD database, including 5,749 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.099 (920 hom., cov: 33)
  • Exomes 𝑓: 0.077 (4829 hom.)
• Consequence: SLC26A9 NM_052934.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.93

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014667511).
• BP6: Variant 1-205918853-T-C is Benign according to our data. Variant chr1-205918853-T-C is described in ClinVar as [Benign]. Clinvar id is 403452.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.165 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC26A9	NM_052934.4	c.2243A>G	p.His748Arg	missense_variant	19/21	ENST00000367135.8
SLC26A9	NM_134325.3	c.2243A>G	p.His748Arg	missense_variant	19/22
SLC26A9	XM_011509121.3	c.1976A>G	p.His659Arg	missense_variant	18/20
SLC26A9	XM_011509122.3	c.1751A>G	p.His584Arg	missense_variant	16/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC26A9	ENST00000367135.8	c.2243A>G	p.His748Arg	missense_variant	19/21	1	NM_052934.4	P1
SLC26A9	ENST00000340781.8	c.2243A>G	p.His748Arg	missense_variant	18/21	1
SLC26A9	ENST00000367134.2	c.2243A>G	p.His748Arg	missense_variant	19/22	5
SLC26A9	ENST00000491127.5	n.1627A>G		non_coding_transcript_exon_variant	11/13	2

Frequencies

GnomAD3 genomes AF: 0.0989 AC: 15044 AN: 152108 Hom.: 916 Cov.: 33

Gnomad AFR AF: 0.169

Gnomad AMI AF: 0.101

Gnomad AMR AF: 0.0753

Gnomad ASJ AF: 0.136

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0325

Gnomad FIN AF: 0.0430

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.0803

Gnomad OTH AF: 0.115

GnomAD3 exomes AF: 0.0718 AC: 18044 AN: 251402 Hom.: 882 AF XY: 0.0700 AC XY: 9512 AN XY: 135868

Gnomad AFR exome AF: 0.177

Gnomad AMR exome AF: 0.0502

Gnomad ASJ exome AF: 0.133

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0326

Gnomad FIN exome AF: 0.0467

Gnomad NFE exome AF: 0.0839

Gnomad OTH exome AF: 0.0859

GnomAD4 exome AF: 0.0767 AC: 111996 AN: 1460760 Hom.: 4829 Cov.: 31 AF XY: 0.0758 AC XY: 55073 AN XY: 726544

Gnomad4 AFR exome AF: 0.174

Gnomad4 AMR exome AF: 0.0527

Gnomad4 ASJ exome AF: 0.133

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0325

Gnomad4 FIN exome AF: 0.0478

Gnomad4 NFE exome AF: 0.0802

Gnomad4 OTH exome AF: 0.0828

GnomAD4 genome AF: 0.0990 AC: 15067 AN: 152226 Hom.: 920 Cov.: 33 AF XY: 0.0946 AC XY: 7039 AN XY: 74442

Gnomad4 AFR AF: 0.169

Gnomad4 AMR AF: 0.0751

Gnomad4 ASJ AF: 0.136

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0323

Gnomad4 FIN AF: 0.0430

Gnomad4 NFE AF: 0.0803

Gnomad4 OTH AF: 0.114

Alfa AF: 0.0884 Hom.: 1565

Bravo AF: 0.106

TwinsUK AF: 0.0806 AC: 299

ALSPAC AF: 0.0781 AC: 301

ESP6500AA AF: 0.168 AC: 740

ESP6500EA AF: 0.0840 AC: 722

ExAC AF: 0.0742 AC: 9010

Asia WGS AF: 0.0220 AC: 76 AN: 3478

EpiCase AF: 0.0930

EpiControl AF: 0.0937

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	0.0010
Dann	Benign	0.25
Eigen	Benign	-2.4
Eigen_PC	Benign	-2.5
FATHMM_MKL	Benign	0.015	N
MetaRNN	Benign	0.0015	T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	0.20	N;N;N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.11	N;N;N
REVEL	Benign	0.26
Sift	Benign	0.66	T;T;T
Sift4G	Benign	0.92	T;T;T
Polyphen		0.0	.;B;.
Vest4		0.011
MPC		0.17
ClinPred		0.0041	T
GERP RS		-10
Varity_R		0.021
gMVP		0.18

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: rs16856462; hg19: chr1-205887981; COSMIC: COSV61605864; COSMIC: COSV61605864;