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rs912147281

chr7-107683356-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP3PP5

The NM_000441.2(SLC26A4):c.918+2T>C variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

SLC26A4
NM_000441.2 splice_donor

Scores

4
2
1
Splicing: ADA: 0.9964
1
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9U:1

Conservation

PhyloP100: 7.27
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PVS1
?
    PVS1 - null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.06487409 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.7, offset of -9, new splice context is: gaaGTaatt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP3
?
    PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_RF.
PP5
?
    PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 7-107683356-T-C is Pathogenic according to our data. Variant chr7-107683356-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 370108.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=5, Uncertain_significance=1, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SLC26A4NM_000441.2 linkuse as main transcriptc.918+2T>C splice_donor_variant ENST00000644269.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SLC26A4ENST00000644269.2 linkuse as main transcriptc.918+2T>C splice_donor_variant NM_000441.2 P1O43511-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0000131
AC:
2
AN:
152186
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000796
AC:
2
AN:
251256
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135800
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
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:
0.00
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.00000616
AC:
9
AN:
1461036
Hom.:
0
Cov.:
31
AF XY:
0.00000825
AC XY:
6
AN XY:
726878
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000895
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0000131
AC:
2
AN:
152186
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74348
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000189

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:9Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Pendred syndrome Pathogenic:5
Pathogenic, criteria provided, single submitterclinical testingBaylor Genetics-- -
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.May 26, 2020- -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpApr 05, 2023Variant summary: SLC26A4 c.918+2T>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Two computational tools predict a significant impact on normal splicing, suggesting the variant abolishes a canonical 5' splicing donor site, while one predicts the variant no significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 251256 control chromosomes. c.918+2T>C has been reported in the literature in individuals affected with hearing loss (Chai_2013, Goncalves_2016, Rentorff_2013, Cengiz_2017), and some of these patients were reported as compound heterozygous with other (likely) pathogenic variants. These data indicate that the variant is likely to be associated with disease. Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitterclinical testingGenome-Nilou LabSep 05, 2021- -
Pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Oct 27, 2021NM_000441.1(SLC26A4):c.918+2T>C is a canonical splice variant classified as pathogenic in the context of Pendred syndrome. c.918+2T>C has been observed in cases with relevant disease (PMID: 23918157, 23336812, 27214836). Functional assessments of this variant are not available in the literature. c.918+2T>C has been observed in population frequency databases (gnomAD: OTH 0.02%). In summary, NM_000441.1(SLC26A4):c.918+2T>C is a canonical splice variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:3Uncertain:1
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsAug 16, 2023- -
Pathogenic, no assertion criteria providedcase-controlGenetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General HospitalFeb 26, 2019- -
Uncertain significance, criteria provided, single submitterresearchLaboratory of Human Genetics, Institute of Biosciences - University of Sao Paulo-- -
Likely pathogenic, criteria provided, single submitterclinical testingGenome-Nilou LabSep 05, 2021- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 27, 2024This sequence change affects a donor splice site in intron 7 of the SLC26A4 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SLC26A4 are known to be pathogenic (PMID: 16283880, 25394566, 26252218, 26445815). This variant is present in population databases (no rsID available, gnomAD 0.006%). Disruption of this splice site has been observed in individuals with Pendred syndrome (PMID: 23918157, 27214836). ClinVar contains an entry for this variant (Variation ID: 370108). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.57
D
BayesDel_noAF
Pathogenic
0.33
Cadd
Pathogenic
28
Dann
Uncertain
1.0
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.92
FATHMM_MKL
Uncertain
0.96
D
MutationTaster
Benign
1.0
D
GERP RS
5.3

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Benign
0.71
SpliceAI score (max)
0.89
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.89
Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs912147281; hg19: chr7-107323801; API