NM_000441.2:c.1826T>G

Variant names:

• chr7-107701849-T-G
• rs17154335
• NM_000441.2:c.1826T>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000441.2(SLC26A4):​c.1826T>G​(p.Val609Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00773 in 1,610,138 control chromosomes in the GnomAD database, including 800 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V609V) has been classified as Likely benign. The gene SLC26A4 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.041 (429 hom., cov: 32)
  • Exomes 𝑓: 0.0043 (371 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 3.74
• Publications: 29 publications found

Genes affected

SLC26A4 (HGNC:8818): (solute carrier family 26 member 4) Mutations in this gene are associated with Pendred syndrome, the most common form of syndromic deafness, an autosomal-recessive disease. It is highly homologous to the SLC26A3 gene; they have similar genomic structures and this gene is located 3' of the SLC26A3 gene. The encoded protein has homology to sulfate transporters. [provided by RefSeq, Jul 2008]

SLC26A4 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• Pendred syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• athyreosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• thyroid hypoplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Specifications for SLC26A4 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -19 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 167 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. Trascript score misZ: -1.7621 (below the threshold of 3.09). GenCC associations: The gene is linked to hearing loss, autosomal recessive, Pendred syndrome, autosomal recessive nonsyndromic hearing loss 4, thyroid hypoplasia, athyreosis.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0016256273).
• BP6: Variant 7-107701849-T-G is Benign according to our data. Variant chr7-107701849-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000441.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A4	NM_000441.2	MANE Select	c.1826T>G	p.Val609Gly	missense	Exon 17 of 21	NP_000432.1	O43511-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A4	ENST00000644269.2	MANE Select	c.1826T>G	p.Val609Gly	missense	Exon 17 of 21	ENSP00000494017.1	O43511-1
	SLC26A4	ENST00000888701.1		c.1826T>G	p.Val609Gly	missense	Exon 16 of 20	ENSP00000558760.1
	SLC26A4	ENST00000888700.1		c.1748T>G	p.Val583Gly	missense	Exon 16 of 20	ENSP00000558759.1

Frequencies

GnomAD3 genomes AF: 0.0404 AC: 6155 AN: 152208 Hom.: 425 Cov.: 32

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0148

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.0301

GnomAD2 exomes AF: 0.0107 AC: 2695 AN: 250926 AF XY: 0.00794

Gnomad AFR exome AF: 0.142

Gnomad AMR exome AF: 0.00726

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000662

Gnomad OTH exome AF: 0.00671

GnomAD4 exome AF: 0.00430 AC: 6268 AN: 1457812 Hom.: 371 Cov.: 30 AF XY: 0.00374 AC XY: 2712 AN XY: 725596

African (AFR) AF: 0.143 AC: 4763 AN: 33292

American (AMR) AF: 0.00798 AC: 357 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39660

South Asian (SAS) AF: 0.000511 AC: 44 AN: 86174

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00867 AC: 50 AN: 5764

European-Non Finnish (NFE) AF: 0.000396 AC: 439 AN: 1108464

Other (OTH) AF: 0.0101 AC: 610 AN: 60246

GnomAD4 genome AF: 0.0406 AC: 6180 AN: 152326 Hom.: 429 Cov.: 32 AF XY: 0.0388 AC XY: 2894 AN XY: 74492

African (AFR) AF: 0.140 AC: 5828 AN: 41556

American (AMR) AF: 0.0148 AC: 226 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5190

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000750 AC: 51 AN: 68022

Other (OTH) AF: 0.0298 AC: 63 AN: 2114

Alfa AF: 0.0153 Hom.: 410

Bravo AF: 0.0458

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.143 AC: 629

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.0132 AC: 1596

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.00131

EpiControl AF: 0.000652

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	5	not provided (5)
-	-	2	Pendred syndrome (2)
-	-	1	Autosomal recessive nonsyndromic hearing loss 4 (1)
-	-	1	Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.039	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	-1.1	N
PhyloP100		3.7
PrimateAI	Benign	0.42	T
PROVEAN	Benign	2.2	N
REVEL	Benign	0.27
Sift	Benign	0.55	T
Sift4G	Benign	0.39	T
Polyphen		0.0	B
Vest4		0.038
MPC		0.011
ClinPred		0.0099	T
GERP RS		5.8
Varity_R		0.093
gMVP		0.57
Mutation Taster		=93/7	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: rs17154335; hg19: chr7-107342294; COSMIC: COSV55916369; COSMIC: COSV55916369;