rs16856462

Variant names:

• chr1-205918853-T-C
• rs16856462
• NM_052934.4:c.2243A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.93
• Publications: 21 publications found

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]

SLC26A9 Gene-Disease associations (from GenCC):

• cystic fibrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 403452.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 rank	MANE	Protein	UniProt
SLC26A9	NM_052934.4	c.2243A>G	p.His748Arg	missense_variant	Exon 19 of 21	ENST00000367135.8	NP_443166.1
SLC26A9	NM_134325.3	c.2243A>G	p.His748Arg	missense_variant	Exon 19 of 22		NP_599152.2
SLC26A9	XM_011509121.3	c.1976A>G	p.His659Arg	missense_variant	Exon 18 of 20		XP_011507423.1
SLC26A9	XM_011509122.3	c.1751A>G	p.His584Arg	missense_variant	Exon 16 of 18		XP_011507424.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC26A9	ENST00000367135.8	c.2243A>G	p.His748Arg	missense_variant	Exon 19 of 21	1	NM_052934.4	ENSP00000356103.3
SLC26A9	ENST00000340781.8	c.2243A>G	p.His748Arg	missense_variant	Exon 18 of 21	1		ENSP00000341682.4
SLC26A9	ENST00000367134.2	c.2243A>G	p.His748Arg	missense_variant	Exon 19 of 22	5		ENSP00000356102.2
SLC26A9	ENST00000491127.5	n.1627A>G		non_coding_transcript_exon_variant	Exon 11 of 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

GnomAD2 exomes AF: 0.0718 AC: 18044 AN: 251402 AF XY: 0.0700

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 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

African (AFR) AF: 0.174 AC: 5826 AN: 33464

American (AMR) AF: 0.0527 AC: 2358 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 3463 AN: 26106

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39674

South Asian (SAS) AF: 0.0325 AC: 2799 AN: 86200

European-Finnish (FIN) AF: 0.0478 AC: 2549 AN: 53378

Middle Eastern (MID) AF: 0.148 AC: 852 AN: 5754

European-Non Finnish (NFE) AF: 0.0802 AC: 89149 AN: 1111140

Other (OTH) AF: 0.0828 AC: 4994 AN: 60332

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

African (AFR) AF: 0.169 AC: 7003 AN: 41512

American (AMR) AF: 0.0751 AC: 1148 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 473 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.0323 AC: 156 AN: 4830

European-Finnish (FIN) AF: 0.0430 AC: 457 AN: 10618

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.0803 AC: 5461 AN: 68000

Other (OTH) AF: 0.114 AC: 241 AN: 2116

Alfa AF: 0.0911 Hom.: 2314

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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
DEOGEN2	Benign	0.032	.;T;.
Eigen	Benign	-2.4
Eigen_PC	Benign	-2.5
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.33	.;T;T
MetaRNN	Benign	0.0015	T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	0.20	N;N;N
PhyloP100		-2.9
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
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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