7-107715429-C-T

Variant names:

• chr7-107715429-C-T
• rs111033255
• NM_000441.2:c.2326C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS2

The NM_000441.2(SLC26A4):​c.2326C>T​(p.Arg776Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00267 in 1,612,960 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R776P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0028 (7 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:8
• Conservation: PhyloP100: 4.26
• Publications: 22 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

Our verdict: Benign. The variant received -8 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 autosomal recessive nonsyndromic hearing loss 4, Pendred syndrome, athyreosis, thyroid hypoplasia, hearing loss, autosomal recessive.
• BP4: Computational evidence support a benign effect (MetaRNN=0.027159065).
• BP6: Variant 7-107715429-C-T is Benign according to our data. Variant chr7-107715429-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43547.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR,AD gene

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.2326C>T	p.Arg776Cys	missense	Exon 21 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.2326C>T	p.Arg776Cys	missense	Exon 21 of 21	ENSP00000494017.1	O43511-1
	SLC26A4	ENST00000888701.1		c.2326C>T	p.Arg776Cys	missense	Exon 20 of 20	ENSP00000558760.1
	SLC26A4	ENST00000888700.1		c.2248C>T	p.Arg750Cys	missense	Exon 20 of 20	ENSP00000558759.1

Frequencies

GnomAD3 genomes AF: 0.00178 AC: 270 AN: 152090 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00293

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00181 AC: 455 AN: 251434 AF XY: 0.00191

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.000520

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00268

Gnomad NFE exome AF: 0.00287

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00276 AC: 4030 AN: 1460752 Hom.: 7 Cov.: 29 AF XY: 0.00265 AC XY: 1926 AN XY: 726758

African (AFR) AF: 0.000747 AC: 25 AN: 33456

American (AMR) AF: 0.000693 AC: 31 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00157 AC: 41 AN: 26126

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.000301 AC: 26 AN: 86236

European-Finnish (FIN) AF: 0.00307 AC: 164 AN: 53414

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5766

European-Non Finnish (NFE) AF: 0.00324 AC: 3602 AN: 1110988

Other (OTH) AF: 0.00225 AC: 136 AN: 60350

GnomAD4 genome AF: 0.00177 AC: 270 AN: 152208 Hom.: 0 Cov.: 31 AF XY: 0.00180 AC XY: 134 AN XY: 74432

African (AFR) AF: 0.000554 AC: 23 AN: 41534

American (AMR) AF: 0.000850 AC: 13 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00283 AC: 30 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00293 AC: 199 AN: 67992

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.00247 Hom.: 2

Bravo AF: 0.00176

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.00200 AC: 243

EpiCase AF: 0.00284

EpiControl AF: 0.00284

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	3	not provided (5)
-	-	3	not specified (3)
-	2	1	Pendred syndrome (3)
-	1	1	Autosomal recessive nonsyndromic hearing loss 4 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.027	T
MetaSVM	Uncertain	0.74	D
MutationAssessor	Benign	1.0	L
PhyloP100		4.3
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.4	N
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.48
MVP		0.99
MPC		0.041
ClinPred		0.019	T
GERP RS		5.8
Varity_R		0.17
gMVP		0.58
Mutation Taster		=22/78	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs111033255; hg19: chr7-107355874; COSMIC: COSV55916018;