rs200664061

chr7-107710175-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_000441.2(SLC26A4):c.2211G>C(p.Glu737Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000126 in 1,606,602 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (1 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:1
• Conservation: PhyloP100: -0.335

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 uncertain in NM_000441.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.02786684).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC26A4	NM_000441.2	c.2211G>C	p.Glu737Asp	missense_variant	19/21	ENST00000644269.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC26A4	ENST00000644269.2	c.2211G>C	p.Glu737Asp	missense_variant	19/21		NM_000441.2	P1
SLC26A4	ENST00000492030.2	n.397G>C		non_coding_transcript_exon_variant	4/6	5
SLC26A4	ENST00000644846.1	c.*113G>C		3_prime_UTR_variant, NMD_transcript_variant	8/10

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000203 AC: 51 AN: 251276 Hom.: 1 AF XY: 0.000214 AC XY: 29 AN XY: 135800

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000158

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000108 AC: 157 AN: 1454322 Hom.: 1 Cov.: 27 AF XY: 0.000117 AC XY: 85 AN XY: 724020

Gnomad4 AFR exome AF: 0.000571

Gnomad4 AMR exome AF: 0.000492

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000769

Gnomad4 OTH exome AF: 0.000416

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152280 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74466

Gnomad4 AFR AF: 0.000650

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000134 Hom.: 0

Bravo AF: 0.000298

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000140 AC: 17

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Pendred syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 28, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	SLC26A4: PM2, BP4 -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 25, 2017

The p.Glu737Asp variant in SLC26A4 has been previously reported in four individu als with hearing loss, one of whom had no inner ear abnormalities. It was not re ported for the remaining three individuals whether or not inner ear abnormalitie s were present (Dai 2009, LMM unpublished data). All these individuals were hete rozygous for this variant and a second pathogenic variant was not identified. Th is variant has been identified in 17/111562 European chromosomes by the Genome A ggregation Database (gnomAD, http://http://gnomad.broadinstitute.org; dbSNP rs20 0664061); however this frequency is not high enough to rule out a pathogenic rol e. A functional study reported that the p.Glu737Asp variant, when expressed in X enopus oocytes, had a reduced rate of Cl(-)/HCO(3)(-) exchange (Dai 2009), thoug h this in vitro assay may not accurately represent biological function. Computat ional prediction tools and conservation analyses suggest that the Glu737Asp vari ant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Glu73 7Asp variant is uncertain. -

Autosomal recessive nonsyndromic hearing loss 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Hearing impairment Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center

Apr 12, 2021

PM2_Supporting, BP4_Supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	-0.070
Cadd	Benign	0.64
Dann	Benign	0.95
DEOGEN2	Benign	0.090	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.032	N
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.028	T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	0.34	N;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.48	N;.
REVEL	Uncertain	0.55
Sift	Benign	0.43	T;.
Sift4G	Benign	0.62	T;.
Polyphen		0.0	B;B
Vest4		0.67
MutPred		0.72		Loss of methylation at K734 (P = 0.0764);Loss of methylation at K734 (P = 0.0764);
MVP		0.84
MPC		0.011
ClinPred		0.0013	T
GERP RS		-2.7
Varity_R		0.041
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200664061; hg19: chr7-107350620;