rs116900495

Positions:

• chr7-103421569-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 8P and 16B. PVS1 BP6_Very_Strong BS1 BS2

The NM_198999.3(SLC26A5):​c.-53-2A>G variant causes a splice acceptor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 1,583,898 control chromosomes in the GnomAD database, including 110 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0074 (8 hom., cov: 32)
  • Exomes 𝑓: 0.012 (102 hom.)
• Consequence: SLC26A5 NM_198999.3 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:6
• Conservation: PhyloP100: 0.747

Genes affected

SLC26A5 (HGNC:9359): (solute carrier family 26 member 5) This gene encodes a member of the SLC26A/SulP transporter family. The protein functions as a molecular motor in motile outer hair cells (OHCs) of the cochlea, inducing changes in cell length that act to amplify sound levels. The transmembrane protein is an incomplete anion transporter, and does not allow anions to cross the cell membrane but instead undergoes a conformational change in response to changes in intracellular Cl- levels that results in a change in cell length. The protein functions at microsecond rates, which is several orders of magnitude faster than conventional molecular motor proteins. Mutations in this gene are potential candidates for causing neurosensory deafness. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Nov 2009]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4.9, offset of 10, new splice context is: tttcccctggtgacactcAGgaa. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• BP6: Variant 7-103421569-T-C is Benign according to our data. Variant chr7-103421569-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 5289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-103421569-T-C is described in Lovd as [Benign]. Variant chr7-103421569-T-C is described in Lovd as [Pathogenic].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00738 (1124/152240) while in subpopulation NFE AF= 0.0118 (801/68008). AF 95% confidence interval is 0.0111. There are 8 homozygotes in gnomad4. There are 527 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC26A5	NM_198999.3	c.-53-2A>G		splice_acceptor_variant		ENST00000306312.8	NP_945350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC26A5	ENST00000306312.8	c.-53-2A>G		splice_acceptor_variant		1	NM_198999.3	ENSP00000304783	P4

Frequencies

GnomAD3 genomes AF: 0.00739 AC: 1124 AN: 152122 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00205

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00675

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00477

Gnomad FIN AF: 0.00782

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0118

Gnomad OTH AF: 0.00526

GnomAD4 exome AF: 0.0115 AC: 16496 AN: 1431658 Hom.: 102 Cov.: 26 AF XY: 0.0114 AC XY: 8117 AN XY: 714134

Gnomad4 AFR exome AF: 0.00201

Gnomad4 AMR exome AF: 0.00421

Gnomad4 ASJ exome AF: 0.00362

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00859

Gnomad4 FIN exome AF: 0.00987

Gnomad4 NFE exome AF: 0.0131

Gnomad4 OTH exome AF: 0.0118

GnomAD4 genome AF: 0.00738 AC: 1124 AN: 152240 Hom.: 8 Cov.: 32 AF XY: 0.00708 AC XY: 527 AN XY: 74442

Gnomad4 AFR AF: 0.00205

Gnomad4 AMR AF: 0.00674

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00477

Gnomad4 FIN AF: 0.00782

Gnomad4 NFE AF: 0.0118

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00981 Hom.: 9

Bravo AF: 0.00721

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 61 Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 27, 2021	- -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Oct 02, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 08, 2023	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 05, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 02, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	SLC26A5: BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Pathogenic	28
DANN	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.76
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.85		Position offset: -12
DS_AL_spliceai		0.99		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs116900495; hg19: chr7-103062016; COSMIC: COSV100098422; COSMIC: COSV100098422;